PT1562932E - 4-tetrazolyl-4-phenylpiperidine derivatives for treating pain - Google Patents

Description

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4-TETRAZOLYL-4-PHENYLPIPERIDINE DERIVATIVES FOR THE

The present invention relates to 4-tetrazolyl-4-phenylpiperidine compounds, compositions comprising an effective amount of a 4-Tetrazolyl-4-phenyl-piperidine Compound and processes for the prevention or treatment of pain or diarrhea in an animal, comprising administering to an animal in need of such treatment or prevention an effective amount of a 4-Tetrazolyl-4-phenylpiperidine Compound. 2. BACKGROUND OF THE INVENTION Pain is the most common symptom for which patients seek medical advice and treatment. The pain may be acute or chronic. Although acute pain is usually self-limited, chronic pain may persist for 3 months or longer and lead to significant changes in the patient's personality, lifestyle, functional capacity, or overall life ÍK. M. Foley, Pain, Cecil River Textbook of Mmicum 100-107, J.C.

Bennett and F. Plum eds., 20 " ed. 1996). The pain has traditionally been treated by administering a non-opioid analgesic, such as, 100-LilPail · '' clOOP acid; > t. 111: 1 ratio of choline and magnesium, alcohol: oxyforformin ibuprofen, diflusinal, and naproxen; or an opioid, such as morphine, hydromorphone, methadone, U.S. Patent No. 6,577, 6,650, U.S. Pat. No. 6,166,039 and US Pat. U.S. Patent 5,849,761, to Yaksh and U.S. Pat. No. 6,573,282 to Yaksh et al., Disclose 1-and 4-substituted piperidine derivatives, allegedly useful as peripherally active antihyperalgesic opiates. 4, U.S. Pat. 6,362,203 B1 for Mogi et al. Discloses 4-hydroxy-4-phenylpiperidine derivatives which are claimed to exhibit a peripheral analgesic benefit. Canadian Patent Publication No. No. 949560 to Carron et al., Disclose piperidine derivatives having substituents at positions 1 and 4, which are independently useful as analgesics. WO 02138185 A2, Dunn et al., Discloses substituted piperidine compounds in positions 1 and 4, which are alleged to be useful as antihyperalgesic opiates. Summary of International Patent Publication WO 99/1003 also discloses piperidine rifixes having substituents at positions I and 4, which are alleged to have been found to be non-toxic. useful as agonists of the opioid receptor.

Analgesics: traditional drugs exert their pharmacological activity as soon as they pass through the blood-brain barrier. But this passage from the blood-brain barrier can lead to undesirable side effects mediated by the central nervous system, such as depression, increased drug tolerance, increased doxycycline dependence, constipation, and unwanted euphoria. There is still a clear need for novel drugs which are useful for the treatment or for the treatment of pain or diarrhea and which reduce or prevent one or more of the side effects associated with traditional therapy for the treatment of pain or diarrhea. SUMMARY OF THE INVENTION The present invention provides compounds of general formula (Ia):

and pharmaceutically acceptable salts thereof, wherein: â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) alkyl, substituted or unsubstituted or substituted by one or more substituents selected from the group consisting of: In one embodiment of the present invention there is provided a compound of the formula: ## STR1 ## in which R 1 represents a hydrogen atom, and R 2 is hydrogen or C 1 -C 4 -alkoxy; or a group of the general formula -L- (CH3) 3 - (C3-C6) -alkyl; â € ƒâ € ƒâ € ƒL is -C (O) -, or -SO-; â € ƒâ € ƒâ € ƒH is H, groups of the formula -C (O) NH2, -CNOHO, of general formula (C 1 -C 4 alkyl), -C (O) N (alk), - (C 1 -C 4 alkyl) uil 0 L · nt

n (CH 2) e > i.i

(½ and R 3 are each independently halogen, C 1 -C 6 alkyl, -O (C 1 -C 6) alkyl, -NH (C 1 -C 3 alkyl), or -N  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ2 or 1% (1) and (2) and (3) and (4) and (4) and (4) (C 3 -C 6 alkyl), R 5 is selected from the group consisting of C 1 -C 4 alkyl, (0) Mr ·························································································· (s): -OH, -OH,% phenyl, naphthyl, anthryl, isopropyl, isopropyl, isopropyl, isopropyl, phenanthral or heteroaryl m is an integer from 0 to 4, n is an integer from 1 to 4, p is 0 or 1, q is an integer from 0 to 3, and er is an integer of 1 to 6. The present invention also relates to compounds of general formula (Ib):

and pharmaceutically acceptable salts thereof, wherein: â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ represents a cycloalkyl-alkyl, one of which is substituted or unsubstituted or substituted by one or more heteroatoms selected from the group consisting of phenyl, naphthyl, anthryl, phenanthryl or feturruryl Lys 5 or 7 atoms in the nucleus), each of which is substituted with one or more groups represented by the symbol R1; The compounds of formula (I) are H, H, H, H, H, H, H,

(O) -, -CO2- or -SO-; or E 1 represents H atoms, -C (O) NHOH, -COCH 2, -CHO, -CN, - (C 1 -C 4 alkyl, -C (O) NH (alkyl: (C 1 -C 4 alkyl)

E1 and R3 are each independently halogen atoms, C1 -C3 alkyl groups, -O (C1 -C4 alkyl) -NH (C1 -C4 alkyl) or -N (

Y1 and Y2 are each H, C1-4 alkyl, YE1 O (C1 -C6 alkyl), -C2 N (a1 C1-6 alkyl), or -CH2 NH (CH2) C4); R5 is -C (O) ΝΗ2, -C m -O- or -C (O) NH (C1-6 alkyl), C (-Q) N

The compounds of the invention may be prepared by reacting the compound of formula (I) with a compound of formula (I): wherein R1, R2, R3, Phenyl, naphthyl, anthio, phenyl, or heteroaryl of 5 to 7 carbon atoms, each of which is represented by the following formula: m is an integer of 0 to 4; n is an integer from 1 to 4; p is 0 or 1; q is an integer from 0 to 3; and r is an integer from 1 to 6. The present invention also relates to compounds of general formula (Ic):

and pharmaceutically acceptable salts thereof, wherein: Ar is a phenyl, naphthyl, anthryl, phenanthryl or heteroaryl group (having 5 to 7 ring atoms), each of which is unsubstituted or substituted with one or more groups represented by H; and G is H, -L- (O) -OC (O) CR 4, -1: -10%. - falgui iísít * ::: -

(CJ-C alquil alquil alquil alkylene), or (C¾-C alquil alquil alquil alkylene), and R representa represents hydrogen, CJ-C alquil alkylene, - (C1-C4 alkyl), -C (O) N (alkyl Qr <

(1) and (b) are independently hydrogen, C1-4 alkyl, -O (C1 -C4 alkyl, -NH (C1 -C4) alkyl, or -N

Citdbi 2! R 4 is H, C 1 -C 8 -alkyl groups -CH 2 O (C 1 -C 4 alkyl) s or -CH 2 NH (alkyl (¾%), R 5 is -NH 2, -C (O) NH 2, -C (O) NHOH, -C (O) NH (C 1 -C 4 alkyl), C (O) N

Cr ": C *; (C1-C4 alkyl), -SO2NH (C1-C4 alkyl), -SQN (C1-C4 alkyl), H, -OH, -CN, -cyclo (alkyl) phenyl, naphthyl, anthryl, phenanthryl or heteroaryl (with 5 to 7 atoms in the nucleus), each of which is unsubstituted or substituted with one or more groups represented by R1: m is an integer from 0 to 4; p is 0 or 1, q is 3 to 3, and r is an integer of 1 to 6. The present invention also relates to compounds of general formula (II):

and pharmaceutically acceptable salts thereof, wherein: Ara represents a phenyl, naphthyl, anthryl, phenanthryl or heteroaryl group (5 to 7 ring atoms), each of which is unsubstituted or substituted with one or more more groups represented by R2; G is H, groups of the formula: wherein R 5 is hydrogen; the symbol i; R1 represents H atoms, C10) groups; â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒR1 â € ƒâ € ƒâ € ƒâ € ƒâ € ƒ- R 2 and R 3 are each independently selected from the group consisting of hydrogen, (C 1 -C 6) alkyl, C 1 -C 4 alkyl, halogen, C1-C3 alkyl, -O (C1-C3 alkyl), -NH (alkyl or -N (alkyl) 2 or R3 represents H atoms, -C1-6 alkyl groups -CH2O (alkyl: C (O) NH2 H, -SO2 NH2, -C (O) NH (NH2), -C (O) NH2, (C 1 -C 4 alkyl), C (O) N (C 1 -C 2) alkyl, -SO 2 NH (alkyl, -SO 2 N (C 1 -C 4 alkyl), H atoms, -OH, -CN, -cycloalkyl, , naphthyl, anthryl, phenanthryl or heteroaryl (having 5 to 7 ring atoms), each of which is unsubstituted or substituted with one or more of R2, m is an integer from 0 to 4; represents an integer from 1 to 4, p is 0 or 1, q is 1 to 3, and 1 is integer from 1 to 6

A compound of the general formula (II) is a pharmaceutically acceptable salt thereof (a combination of 4-tetrazolyl-4-ferrylylpyridines The present invention also provides compositions comprising an effective amount of a 4-Tetrazolyl-4-phenylpiperidine Compound and an acceptable carrier or excipient The present invention is also directed to kits which comprise a package containing an effective amount of a 4-Tetrazolyl Compound The present invention further provides methods for the prevention of pain or diarrhea in an animal which comprises administering a compound of the formula effective amount of a phenylpiperidine. The present invention further relates to the treatment of pain or of the day administration to a desired amount of a 4-Tetrazolyl-4-compound having as its subject matter a method of treating an animal, comprising administering to it a compound of formula The present invention further provides methods for stimulating opioid receptor function in a cell comprising contacting a cell capable of expressing an opioid receptor with an effective amount of a 4-Tetrazolyl-4 compound The present invention further provides methods for a pharmaceutical composition comprising the step of mixing a 4-Tetrazolyl-4-phenylpiperidine Compound and a carrier or a pharmaceutically acceptable salt thereof. excipient from the pharmaceutical point of view. The present invention may be better understood with reference to the following detailed description and the illustrative examples which are intended to exemplify non-limiting embodiments of the present invention. 4. Detailed Description of the Present Invention 4.1. Definitions

As used herein, the terms used above have the following meaning: "-alkyl" refers to a cyclic, unbranched or linear cyclic hydrocarbon chain having 1 to 3 carbon atoms. Representative examples of straight chain and branched chain C 1-A-alkyl groups are as follows: S: &gt; ρ r Oip 11 P P 1 1 * v--Π Π Π Π Π Π c c c c c c c c c c c c c c c c c c c c c c c c c c c. 'ç: Lfç'à-.i or? having 1 to 4 carbon atoms. Representative examples of groups - δϊίο'οΐΐίί C: - · Γ. ·. of chain j irosc. ;; include methyl, -ethyl, -n-propyl and -n-butyl groups. Representative examples of β-groups of the β-pc chain of the β-peptide chain are the β- The term "monocyclic" means a straight or branched non-cyclic cycloalkyl chain having from 1 to 6 carbon atoms. Representative examples of straight-chain groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl. Representative examples of branched C1-6 alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert -butyl, -isopentyl, -nopopentyl, -1-methylbutyl, -2-methylbutyl, -3-methylbutyl groups , -1,1-dimethylpropyl, -1,2-dimethylpropyl, -1-methylpentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -1-ethylbutyl, -2-ethylbutyl, - 3-ethylbutyl, -1,1-dimethylbutyl, -1,2-dimethylbutyl, -1,3-dimethylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl and -3,3-dimethylbutyl. &quot; -alkyl-Cu &quot; means a straight or branched non-cyclic hydrocarbon chain having from 1 to 10 carbon atoms. Representative examples of straight-chain 11-: alkyl groups include methyl, -ethyl, -n-propyl, msPButiX, n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, - n-nonyl and -n-decyl. Representative examples of branched C1-6 alkyl-C1-8 alkyl groups include -isopropyl, -sec-butyl, -promopropoxy, ethoxy; 3-methylbutyl, -1,1-dimethylpropyl, -1,2-dimethylpropyl, -1-methylpentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -1- -ethylbutyl, -t-ethoxybufen-4-yl, (1), (2), (3) and (4). X-w V, ν ΐ · diylf: ν.1X1!%; *. - χ · t χΧο: &gt; - 1-Uis:: χΧ-h & i! Ϊ́ί: #

(s, 1H). -; -νΓ>: -: - - - - - - - - - - - - - s x, x, x, x, y, x, x, &lt; X-X-X-X-X-X-X-X-X-X-X-X-X-X-X ·· X X. I - 1: ¾ pd X ': ¾

- ·: &lt; ·.! C--Cal-Cal alkylene means a bivalent, non-cyclic, linear or branched hydrocarboxylic chain having from 1 to 4 carbon atoms, Representative examples of straight chain C1 -C5 -alkyl groups include -CH2 -, - (CH2) 2 -, - (CH2) 3 -, -CH2 -CH2 -CH3 Representative examples of branched-chain C1-C5 alkylene groups include -CH (CH3) -, -C (CH3) 2 -, -CH (CH3) CH2-, -CH2 CH (CH3) -, -CH2 C ( CH3) 2, -C (CH3) 474 ---, -CH (CH3) CH (CH3) -, -CH2 C (CH3) and â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ and -CH (CH3) CH2 CH (CH3) C 1 -C 6 alkyl groups include cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl and -cyclooctyl-heteroaryl groups (5 to 7 ring atoms) which means an aromatic heterocycle ring in which at least one ring member is selected from the group consisting of nitrogen, oxygen and sulfur. A heteroatom independently selected from nitrogen, oxygen and sulfur. The heteroaryl ring (having 5 to 7 atoms in the nucleus) ΡόηΧ.χΐρ by the carbon atom, Xi-yx-i. 5 to 7

Representative examples of heteroaryl atoms in the nucleus) include the pyridyl, -furyl, &quot; i c faith ......... 5-oxo-1-oxo-1-oxo-1-pyridyl. i X o &quot; t ie: sodô | 1, 2, 3, 4, 5, 6, 6, 8, '·:·· 1 :··; p '; (i.e. Eur-lex.europa.eu eur-lex.europa.eu Eur-lex.europa.eu eur-lex.europa.eu Eur-lex.europa.eu eur-lex.europa.eu i &gt;. . &Quot; . ~ P:::: /. , ·· \? 1, 1, 1, 2, 3, 4, 5, 6, \ *. ·. Α. · 'Λ *>. d, V and ···. v, v, v and v -triazine. means -F, -61, -9r or -I. The term &quot; animal &quot; includes, but is not limited to, an ogpa, monkey, chimpanzee, baboon, horse, sheep, pig, chicken, turkey, koala, cat, dog, mouse, rat, rabbit, guinea pig and humans. The phrase &quot; pharmaceutically acceptable salt &quot; as used herein is a salt formed from an acid and a basic nitrogen group of a 4-Tetrazolyl-4-phenylpiperidine Compound. Illustrative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bis-suifate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e. salts The term &quot; pharmaceutically acceptable salt &quot; also refers to a salt of a 4-tetrazolyl-4-phenylpiperidine cupupates with a functional group; acid, such as an acid functional group carboxylic acid hydroxides and an organic base or the like, and the alkali metal salts thereof, such as sodium, potassium and lithium, alkali earth metal hydroxides such as sodium, potassium and lithium. such as calcium and magnesium; hydroxides of tttt-meth such cone, aluminum and zinc; ammonia; and organic arnicas, such as, e.g. I sofi ti Mus

; S and X; ethylamine; 1α, 13β-triethylamine; mono-, bis- or tris- (2-hydroxy- (alkylsulfonyl) -sulfonyl), such as mono- or tris (2-hydroxyethyl) amine, 2-hydroxy- tert-butyamine or tris (hydroxymethyl) methylamine, N, N-di- (lower alkyl) -N- (hydroxyl- lower alkylamines, such as N, N-dimethyl- N - (2-hydroxyethyl) amine or The term &quot; treating &quot; or &quot; diarrhea treatment &quot; includes decreasing the severity or cessation of pain In one embodiment, &quot; treatment &quot; includes inhibition, for example, reduction of all frequency of episodes of pain or diarrhea.

The terms &quot; prevention &quot; and &quot; prevent &quot; pain or diarrhea includes avoiding the onset of pain or diarrhea. The phrase &quot; opioid receptor &quot; means a δ-opioid receptor, a Î ± -opioid receptor, a receptor for or an ORL-1 receptor. The phrase &quot; effective amount &quot;, when used in connection with a compound of &lt;: n: r-sv; o: · =; - Ί-; ·: ··; · mm; (means an amount of the 4-Tetrazolyl-4-phenylpiperidine compound which is useful for the treatment of the prevention of pain or diarrhea in an animal or in the stimulation of opioid receptor function in a cell. quot; effective amount &quot;, when used in connection with another therapeutic agent, means the amount to provide the therapeutic effect of that therapeutic agent.

When a first group is &quot; substituted with one or more &quot; second groups, each one or a half of the first hydrogen atoms is replaced by a second group.

In one embodiment, a first group is substituted up to three second groups.

In another embodiment, a first group is substituted with one or two second groups.

In another embodiment, a first group is substituted with only a second group. 4.2 Compounds of 4-Tetrazolyl-4-phenylpiperidine

As mentioned before, the present invention relates to 4'-tetrazolyl-4-phenylpiperidine compounds of the general formula (Ia): ## STR3 ## The pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts, pharmaceutically acceptable salts, pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable salts thereof.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperazine Compounds of General Formula are those wherein G is H.

In another embodiment, the 4-Tetrazolyl-4-Phenylpiperidine Compounds of Formula (Ia) are those wherein G is -L- (<1) and i is a group of formula -C (O) -.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of the formula (OM) are those wherein G is -O-, -O- or - S0-.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those in which G is -L- and fq is H.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is -L- (CH 2) n CG 2 R 4 and FU is

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (I ') are those wherein G is -L and M is a group of the formula -CH 2 O formula

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are &quot; in which G is a group of the general formula and Fb represents a group of CbvbH (C 1 -C 4 alkyl) or (C 1 -C 4 alkyl);

In another embodiment, the 4-Tetrazolyl-4-isopropylidene Compounds of general formula: wherein: G is - (C 1 -C 5 alkylene) COCR 4.

In another embodiment, the 4-Tetrazocyll-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is a group

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ia) are those wherein G is CH (CH 2)

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is - (CH2) rbbXaFbF

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is a group of Formula

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula I &amp; 1 are those wherein G is a group of the general formula - (Ia) are those in which G represents a group of the general formula. it's the

R 4 and R 4 are as defined above, the compounds 4and 4-tetrazolyl-4-phenylpiperidine of formula (1) are those wherein G is -L- (CH 2) 2; R5 is a group of the general formula (I): ## STR1 ## in which R 1 is hydrogen. (C 1 -C 4) alkoxy, -C (O) N:

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is -O-O) (04-0: 1: ¾) and the symbol R 5 represents a group - SO 2 NH (C 1 -C 4 alkyl) or - SO 2 N (C 1 -C 4 alkyl) s ..

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is -L- (CH 2) n R 5 and R 5 is - NH2 OH.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is -L-,;,,, ½ 1, and L is a group of formula -C (Q) -.

In another embodiment, the 1-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is -L- (CH 2), -1, and L is a group of Formula -SO2- or -SO-.

In another embodiment, the phenylpiperidine compounds of the general formula (La) are those wherein G is -CH 2 - (alkylene), the compounds 4-tetrazolyl-4-phenylethanol in general a compound of the general formula: wherein: G is -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2- general of those in which G is a group of the general formula tC8b-Hw3 &gt;

In another embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of formula (Ia) are those wherein G is a group of the general formula. - CH, d,

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is a group of Formula

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is - (Ctb) Srfq &lt;

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is - (C1-6 alkylene) and R5 is C (O) NH2, -C (O) NHO, -C (O) NH (C1-6 alkyl) or -C (O) N (C1-6 alkyl)

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is a group of the formula and wherein R1 is

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those in which G is a group of general CH 2 C (O) N (CH 3)

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (I) are those wherein the G-system is -q 1¾) - and R 5 is -C ) NH2, -C (O) NHOH, -C (O) NH (C1 -C6 alkyl) or -C (O) N (C1-6 alkyl)

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (la) are those wherein G is a group of the formula bc-tb and R5 is a group of the general formula -C (O) NH2, -C (O) NHOH, -C (O) NH (C1-C4 alkyl) or -C (O) N (C1-C4 alkyl)

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is a group of the formula - (CH 2) 3 and R 1 is - C (O) NH2, -C (O) NHOH, -C (O) NH (C1 -C4 alkyl) or -C (O) N (C1 -C4)

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is a group of the general formula and R 1 is - D) NHOH, -C (O) NH (C 1 -C 4 alkyl) or -C (C) N (C 1 -C 4 alkyl)

In another embodiment, the compounds of the 4-Tetrazolyl-4-methylpiperazine (general) are those wherein p is C.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula Ila are those wherein p is 2.

In another embodiment, the 4-Tetrazolyl-4-compounds of general Pis) are those wherein p is I and the carbon atom to which Fd is attached, is in a (R 1) configuration.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein p is 1 and the carbon atom to which R 3 is attached is in a (S) configuration.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein p is 1 and R 3 is C 1 -C 3 -alkyl.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein p is 1 and R3 is

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein p is 1 and p is 3; R 1 represents a C 1 -C 3 alkyl group and the carbon atom to which R 3 is attached is in a (R) -cyclopentyl.

In the context of the foregoing, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (I) are those wherein p is 1.beta.-isobenzo-R3 is -CH3 and to which R3 is attached, is in a (R) configuration.

In another embodiment, the Î ± -tetrazolyl-4-phenylpiperidine compounds of formula (Ia) are those wherein p is 1 and R3 is C1-3 alkyl and the carbon atom to which the symbol R3 is connected, it is in an (S) configuration.

In another embodiment, the 4-oetrazolyl-4-phenylpiperidine compounds of formula (la) are those wherein p is 1 and R 3 is -CH 3 and C 3 to which R 3 is is in an (S) configuration.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein q is 0.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein m is 0.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein m is i.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein m is 0 and p is 0.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein m is 1 and p is 0. The 4-Tetrazolyl-4-

(Ia) are those wherein m is 0 and q is 0.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein m is 1 and q is 0.

In another embodiment, the 4-tetraazolyl-4-phenylpiperidine compounds of formula (la) are those wherein m is Xó p is 0 and q is O.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein m is 1, p is 0 and q is 0.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein R2 is -Br, -Cl, -I or -F.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein R2 is -O-

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of the general formula are those wherein R2 is C1 -C3 -alkyl.

In another embodiment, the 4-Tetrazolyl-4- hand tqitirlírs ® qoa the symbol p; represents a group of the formula: wherein R 1 is hydrogen; the compounds of 4-Tetrazolyl-4-phenylpiperidine of the formula ## STR1 ## are those in which R 3 is - (C 1 -C 4 alkyl) Br, -Cl, -L or -F.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (1) are those wherein Mm is - (C C-C --C)) group.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein R1 is C1-C3-alkyl.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those in which R3 is -NH (C1-4 alkyl), or -N (C1 -C3) alkyl ) 2 -

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein cm is H.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein E 1 is -C (O) NH 2, -C (O) NHOH, -C (O ) NH (C1-C4 alkyl) or -C (O) N (C1-C4 alkyl) 2.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Is) are those wherein MM is a group of the formula -C (O) N (MMMi) 2

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of general formula (Ia) are those wherein m is a group of formula

C (O) N

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are asymmetric compounds wherein 4-Tetrazolyl Compounds are represented by the following formula: -4-phenylpiperidine derivatives of formula (Ia) are those in Scheme B; represents a group of formula C (O) NH; .

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein R1 is -COOR4.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein R1 is -CHO.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein R1 is -CN.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein R1 is. represents a - (C1-C4 alkyl) group.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (IIa) are those wherein B is a group of the general formula

In one embodiment, those of 4-tetrazolyl-4-phenylpiperidine of the general formula ## STR1 ## wherein Pt; represents a group C &gt;

In another embodiment, the 4-tecrazolyl-4-phenylpiperidine compounds of general formula (ua) are those wherein v is hydrogen. represents a phenyl, naphthyl, anthryl or phenanthryl group.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine compounds of Formula (a) are those wherein Ara is a heteroaryl group (having 5 to 7 ring atoms).

In another embodiment, the 4-cetrazolyl-4-phenylpiperidine compounds of formula (Ia) are those wherein Ar1 is substituted by one or more groups represented by the symbol 1 '.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein Ar2 is phenyl, naphthyl, anthryl or phenanthryl.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein Ar: - represents a heteroaryl group (having 5 to 7 carbon atoms;

In another embodiment, the Î ± -r-ptonc; those of 4-tetrazolyl-4-phenylpiperidine of the general formula are those wherein m is 0; is bqfep: wherein R3 and R4 are as defined above.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds and the general formula ## STR1 ## are those wherein c is 1, is phenyl.

In another embodiment, the compounds 4-ethylbenzylphenylpiperidine of formula (1) are those wherein the symbol .ar .; represents one. cyclohexyl group.

In another embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds and the general formula are those wherein M- represents a cyclohexyl group and Mn represents a phenyl group.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is H and p is 0.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is H and q is O.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is H and m is 0.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are α-oleyl wherein G is H and ο οΐοΐόοίο m is 1.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is H and Ar and Att are phenyl.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is Η, p is 0 and q is 0.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein the symbol G is H, p is 0 and m is 0.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is Η, p is 0 and m is 1.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is Η, p is 0 and A 1 and A 2 are phenyl.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is Η, p is 0, q is 0, and m is 0. oo-qo ·:;: · :; The 4-Tetrazolyl-4-phenylpiperidine derivatives of Formula (Ia) are those wherein G is Η, p is 0, q is 0, and m is I.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) in which the compound G is p is 0, q is C, and A 1 is as defined above. phenyl.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is Η, p is 0, q is 0, m is 0 and the symbols / a ;; and Ar: represent a phenyl group.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ia) are those wherein G is Η, p is 0, q is 0, m is 1 and Ar and Ar2 are phenyl.

Exemplary compounds of 4-tretazolyl-4-phenylpiperidine of formula (II) have the following structure:

and the pharmaceutically acceptable salts thereof, wherein G and R 1 are represented by the following: ## STR1 ## ..... H-Hysulfenyl; * ·: CH ·; ('i ΙΌ').

.EASE-PEE-, PEC, EH-: 1 C *. E.Sf &quot; &quot; : E: -EP S-; S-P-E /; i-4 EMI &quot; - C (P): - (CH2) m - , P, and P '• SOE-E-E-PlE-E 1 • • • • • • • • • • • • • • • • • • • • • • • • S: &lt; '... &lt;.' vp {':' 'VPPPE: Pw :::::: 4,4.: 44., - 4. ... w / H EEL 444; ::: PPSE P: ;; 4-4 F v>: 4: - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - • SEE - • ΡΡΗΡΕίΡΕΐΕχ -41 s ....... 1 •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• - (CH 2) p -E 1 O, .EH ::: AAT -H -C (O) NH 2, .................... , Λ Λ Λ Λ Λ PE PE PE PE PE PE PE ESP ESP ESP ESP ESP ESP ESP ESP ESP ESP ESP ESP ESP ESP ESP ESP ESP ESP - P D1: EP :; .......... λ'αρε ................... 5 ..... - 4,4: 4 Ε4Ε ε: EA :::: - OpPl-h --- .. ......... ,,,,,,,,,,,,,,,,,,,,,,,, ... ........................ 4 ..... • v. psp · ;;;;, Ç. Cp; E &lt; / RTI &gt; 4 &quot; s. &gt;.(I.e.; - CIO! -EEE-CaEI-PíScBs - P P IH ;: n: YpPp- ;. Λ;; · · · · ·. (I.e., a), and (b). • V 0) EB ;; s ....... 1 ------ \ ΥόΗ> ·· 1 ················································ 4: Ep Hip SBP - 4: 1. (I.e. ·' AND·-:. &Lt; tb &gt; 1 · "4 CCl € 4 € 0: 4 pC4: CCI: 4" C C Π Pz,. 1 EPS; ·· '< : P = -0 ..., 0 ~ -p: Y '> P p -i ... § A & J' '; - EOE: / 4 PCOPOÍEH! ;; - P: -; E. 1 SP P; α 1;. '': &quot; · '' E ... ·. . f '' · ... p '· - ,; 0V: Y' ΐ Υ'ί · ':: · ESP - ics &gt; (s, 1): S: p; j

WCR-ACX; :: 1 -CHO ACY .......... i ..............: -H i -CN i. &gt;

I

ADA ADB '] .............. "C (O) -CN ADC'. ..............- TcWiSlowr ™™™ "; ADD "(CH 2): C (O) N (CH 2) 2 - C (O); ADE -CN ADF -ch2cc2ch3, -CN ADG-CM, -C (CH 2) ) CSCfCCC I -CN I • Ãct: C • '; CC ·' ........... Ϊ .....: ------------ f --- - (CCl C ^ DjCCCCCC ClCCsCCsCCsCCsCCsCCsCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC CH3 - CH3 - CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 - - - - - - - - - - - - - - - - - - - - - - - - - - Compound ## STR8 ## Compound ## STR8 ## Compound ## STR8 ## Compound ## STR8 ## Compound ## STR8 ## (1) and (2) and (3) and (4) and (4) and (4) : · · C C C C C C C C C C C C C C C C C C C C ΡΗ ΡΗ ΡΗ ΡΗ ΡΗ ΡΗ ΡΗ ΡΗ ΡΗ ΡΗ ΡΗ ΡΗ: C h; Α!: Ε & &quot; VCH ------------ ------------------------------------------------ (O) NH (CH3) AEM -CHSCCO) 3 -CH2C (O) NH2-C (O) NH (CH3) ) AEN -C (O) CH2 NHCH2 CH2 CH3 -C (O) NH (CH3): Mw * cm-1 ALF &quot; &quot; C (O) N (CHâ,,) â,,Hâ, â,,NHâ,,Oâ,,; &gt;; C (O) N Fc C -C (O) N GCH;: F ;; [................. AFK .......... .......... - - - i ~ C (Hi A AGmb; | ------------------------------ Eur-lex.europa.eu eur-lex.europa.eu - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ------------------ Τ_Γ "Γ: ---------------; | -FT H Á? C 'H: · * (1), and (2) and (3), and (4). ............ -CH 2 C (O) n H 2 -CH (C 1 -CH 3) (1), and (2), and (2), and (3) are given in Table 1 below. The term &quot; W &quot; and &quot; W &quot;

Compound Nc. G:

AG D

AGE

AGF

AGI (CH; (W) W f f f ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ ΗΝ CN ΗΝ ΗΝ ΗΝ CN CN CN CN CHâ,,, CHâ,,, R-1, R 2, R 2, R 3, R 4, "CH3 CH3 CN

AGK

AGL

D w ^ XXXXXNV \

AGM

-ch2so2n \ m? A -Ml i / \ £ ΗΊ ΨΜΜη \ *

X is H N-GH-s is 0. .. n f -G-R &gt; ·: · .. &gt; ' .

AGR: · ·: {U j

* "Λ i-H

| Ν Ν Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Ν Ν Ν Ν Ν Ν Ν Ν Ν! N, N-diisopropylcarboxylic acid; (1) (1): wherein R 1 is as defined in claim 1, wherein R 1 and R 2 are as defined in claim 1, v ί ΐ.ϊίΰ f ../¾¾ ....... C- &quot; N _J ì -------------------------- ------------------- -.............................. ..................... . - - - - - - - - - - AHS &quot; CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH C The term &quot; H &quot; . f / ¾¾ 1 \ ss ^ | (CH3) 2, CH3, CH3); II / ¾¾ '&quot; &quot; O-: py' $ .................... Λν-rrfT .. AHV - € 1; € I: I II / ¾¾ 1 | AHW: - (CH2):: ν, Α:;: ΑΗΧ! | li / ¾ ^ j | Eur-lex.europa.eu eur-lex.europa.eu /? (i.e. f. -J i; . * B;; '¾ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ: (1) (1) (1) (2) (2) (2) The invention relates to a process for the preparation of a compound of the formula: ## STR1 ## wherein: and in the presence of a compound of the formula: ## STR4 ##

AIG ΑΙΗ IY I: ic ic W W W W W W; M p i \\ ww \ v 'i 0 &quot; B, C, B, C, B, C, · H. / V | and / or p-x-f-M-P,

n &gt; w vwvvwv. 3! - - - - - - - - - -

V

AIO .or n &lt; &gt;

Ο ....... dl &quot; OHPit

V π 5V ο

If &lt; 0 - The awmw, d · :: .-::. , r:. (_ Λ Λ Λ (((((((((((((((((((((((((((((((((((((((• • • • • • AIV w ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ ΤΪΜ. (CH 2) dtHS CH 2 CH 2 -CH (O) NHCH 3 Ay; 5. • x \; · 't' '* b ·:. . S; v j-d; (R) -cycloalkyl; · '&Quot;1;' ij ... 1 -C (O) N (CH3) ;; ii n / λ 1 - |% SO-H v: diHbbCl2; ϋ D ISS. / \; I-N-1! &quot; N- [Î ± -cyclohexyl]

The present invention further has general formula (1b): object compounds of and pharmaceutically acceptable salts thereof, wherein Ar, A, G, m, p and q are as defined above.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperazine Compounds of Formula (Ib) are those wherein G is H.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is -L- (C: H:

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is -L- (Gib) .gl (O:) (¾ and L is -C (O) -.

Act? In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is a group of the general formula -L-ΑΑνΑ ut CGGDlis and L is -C - or -SO-. phenylpiperidine of formula (Ib) are those wherein the symbol G is -L-C (O) CR1 and Î ± g is an ito® of H.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is -O- and R4 is alkyl &quot;

Cio

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Tb) are those wherein G is -L- (CH 2) n C (O) CH 2 and CH 2 represents a group of C1 -C4 alkyl).

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is -L-

Wg and the symbol represents -CH 2 NH (C 1 -C 4 alkyl) or -CH 2 N (C 1 -C 4 alkyl) 2.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is - (C 1 -C 4 alkylene) R 5.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of general Formula (Ib) are those in which O -sixyl.q: G represents a group of formula

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is a group of general formula:

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is a group of the formula:

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is a group

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is a group

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is - (

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is -

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is a group

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is -

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine compounds of Formula (Ib) are those wherein G is a group of formula

In one embodiment, the 4-Tetrazolyl-4-ylpiperidine Compounds of Formula (Ib) are those and G is - (CH2) 5 -COOR4.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are wherein G is a group of the general formula -L-Kbb; b and q is a group of formula

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is a group of the general formula and pq is -C (O- C (O) NHOH, -C 103 NH (C 1 -C 4 alkyl) or -C (O) N (C 1 -C 8 alkyl)

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of formula (Ib) are those wherein G is -L- (CH 2) n R 5 and PU is - SO 2 NH 2, - SO 2 NH (C 1 -C 4 alkyl) or "SCUN (C 1 -C 8 alkyl)

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is -L- (CH 2) n -P 5 and R 5 is a group of formula General • Uótóbj.N.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is a group of formula (I) L is -C (O) -.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of the general formula (Ib) are those in which G is a group of Formula-L-symbol L is -SO2- -.

In one embodiment, the compounds: 4-tetrazolyl-4-phenylpiperidine of general formula (Ib 5 are those wherein p is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein p is 1.

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of general formula (Ib) are those wherein p is 1 and the carbon atom to which δ is attached is in an (R) configuration.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein p is 1 and the carbon atom to which R 3 is attached is in an (S) configuration.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein p is 1 and R3 is -C1-3 alkyl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein p is 1 and cyberbin R3 is -Cl *

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein p is 1 and ω is a C1-4 alkyl group; and the carbon atom to which R3 is attached is in a (R) configuration.

In one embodiment, the 4-Tetrazolyl-4-Fe-Compounds of general formula rjoq are those wherein p is 1 and the symbol is -CH 3 and the carbon atom to which R 3 is is connected, is in a configuration (! 'ç,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein p is 1 and R3 is -C1-6 alkyl. and the carbon atom to which R3 is attached is in a UI configuration).

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein p is 1 and R3 is -CH3 and the carbon atom to which R3 is is in an (S) configuration.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein q is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein m is 0, and the 4-Tetrazolyl-4-phenylpiperidine compounds of formula (Ib) are those wherein m is I.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein m is 0 and p is 0.

In one embodiment, the phenylpiperidine compounds of formula (Ib) are those wherein m is 1 and p is 0.

In one embodiment, 4-Tetrazolium i. 1-4-phenylpiperidine of formula (Ib) are those wherein m is 0 and q is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein m is 1 and q is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein m is 0, p is 0 and q is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein m is 1, p is 0 and q is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein R2 is -Br, -Cl, -I or -F. Accordingly, the compounds and 4-tetrazolyl-4-phenylpiperidine of general formula (III) are those wherein R2 is -O- (alkyl,

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of general formula (Ib) are those wherein R2 is -C1-3 alkyl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein Fq is -NH (C alquilo alquilo alquilo alkyl) or -N (C alquilo ((alkyl Igm 3;

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein R 3 is -Br, -Cl, -I or -F.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein R 3 is a - (C 1 -C 3) alkyl group).

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein R 3 is -

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein R3 is -NH (alkyl or -N (alkyl) -bb: 2-

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein R4 is H.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are mmykolase for R; represents a group of the general formula -O (O) -C (O) NHCH (NHm)

In one embodiment, the 4-tetrazolyl-4-compounds of general formula (Ib) are those wherein the symbol ti represents a group of general -C (O) N (ρ)

In one the 4-tetrazole compounds. 11-4-phenylpiperidine derivatives of general formula (Ib) are those wherein R1; represents a group of the formula C (O) N Ku.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib): are those wherein R 5 is -C (O) NHCH 3.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein R 1 is C (O) NH (CH 2 CH 3).

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein R 1, is -COOR 4.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein Ib is -CHO.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein δ is -CN. In one embodiment, the 4-phenylpiperidine-4-sulfonic acid compounds of general formula (Ib) are in which R 1 is - (a)

In one embodiment, the 4-Tetrazolyl-4-Phenylpiperidine Compounds of Formula (Ib) are those wherein B: s is a group of the general formula 0 ts mk 0 f * · η f · ν ··· 0 Ϊ ϊ Η Ν Ν Ν Ν Ν Ν Ν Ν Ν Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein â € ‡ â € ‡ â € ‡ represents a -

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein Ar1 is phenyl, naphthyl, anthryl or phenanthryl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein Ar1 is a heteroaryl group (having 5 to 7 ring atoms).

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein Ar1 is substituted by one or more R2 groups.

In the embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of general formula (Ib) are those wherein A 'is phenyl, naphthyl, anthryl or phenanthryl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Xb) are those wherein the symbol &quot;;; represents a heteroaryl group (having 5 to 7 carbon atoms).

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of general formula (Ib) are those wherein Mg is substituted by one or more groups represented by R2-

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein Ar; and Ar2 represent phenyl groups.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein represents a cyclohexyl group.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein Mg is cyclohexyl and Ar2 is phenyl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is H and p is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib: are those wherein G is H and H is q,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of general formula: wherein: G represents an atom of the symbol m0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (-b) are those wherein G is R and m is 1.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is H and Ar and Ar2 are phenyl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is Η, p is 0 and q is 0.

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of formula (Ib) are those wherein G is Η, p is 0 and m is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is Η, p is 0 and c is m is I.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is an e and p is 0 and b and u are a phenyl group.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G is K, p is 0, q is 0, and m is 0.

In one embodiment, the difficult 4-tetrazolyl-4-1-hydroxypitoxy compounds of formula (Ib) are those wherein G is B and P is 0, 0. symbol i | is 0 and m is 1.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is Η, p is 0, q is 0, and Ar and Ar 2 are a phenyl group.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is Η, p is 0, q is 0, m is 0 and Ar1 and Ar2 are phenyl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ib) are those wherein G is Η, p is O, q is O, m is Br 1 and Ar 2 represent a phenyl group.

Illustrative compounds of 4-tretazolyl-4-phenylpiperidine of general formula (Ib) have the following structure:

in which the symbols G and e and the secs under the point of view are represented by the following

ΒΆΑ | ... â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ EAE - (CH2) p (O) NH2 | -H SAP O '. ·· &gt;. ΑΠΗ ν.'ϊ'lis

HHAIOHAA bai &gt; \ &gt;. - &gt; &gt;, &gt; &gt; * Dtsc: G; d :: HjCB; : CS {:] ρίΡΗΑΑ iPHl -11: 1111. CS

• c H ϊ ..... BAN [iit: - picppsPOrAtsic, | -H BAP η · '- · - · WV: C Ciai Pn AI' -Bi: Γ s s''ACACACACACACACACAC SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP SAP , '; ; Cl I Hl BAS B (B) BAT .........: ......... (O) NH 2 --C (O) - (CH 2) 2 - ΑΙΑ) r. ; Gs. - ClSlPvp: P SB si; (1): wherein R1, R2, R3, R4, R4, R4, R4, R4, R4, 1 1 BAY - • .CB: ;; ·!! A (0) X ΗΒΒΧ} S ............, v, '' '' '' '' '' '' '' '' '' '' '' '' '' ... '' '' '' ' Α Β Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α, (B):::::::::::::::::::::::::::::::::::::: , ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ ΧΑΗ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ; • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • - AHAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA •• 'HA {D | HA 1 i ........ i BBG -aha mb aba 3 • ΑΌ ·; · (; Ηλ ........ 1 i L________: 1; ... ...... EBB-BA AHAA ^ AaA 1 AAACI! ....... ™ n:. &gt;: &quot; (I.e. BA! • CBbOB-BBB BBB w V: A, < , 'V ·; A '', \ vh :; f v ··., VV · 'A-: Av; · 1! ........ i ...... j Ά vOj AAA: AHBBAAÀ i- j AAí-: CB4 \ ........ i æ AAAAAA j j &quot; B ^ JvBB; Η X A · Η: Ϊ i «ΒΟ, ΒΙΑ; \; ···! H'HA; A A A I - ···································································: 1, 2, 3, 4, 5, 6, 7, 8, 8, 8, 9, 10, . &lt; · Ν · θΑΧ; Αί: ·! '!. ::: ..; &gt;

Ij., Ç "; (1) BCD: 1 BCE i BCF ...: i {i ....... ί ............ i ECG -CBj-; C (0 :  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒBBB: :  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ- (i.e. .. | ...........: -CHu .............. 1 BCO '' ' B, ..., B, ..., B, B, B, B, B, and B: BB-B; ······························································ (BCR BCS), and (B) BCS (B). CHO s ί BCU ....... ί '· ΒΒ1: · ίΒ'ΒϊΒ; · Β ·: -CHO $ \ BCV: i HBEBB Β C Β CHs ΐ' BHB Βν! 'Βί'ΐ' CH : BMBB: B-.Bis w Bi J-: &quot; B: BO .. BB BB ..... BB-

Compound No. G

(CH 3) 2 - (CH 2) 3 - (CH 2)

B FF &quot; CHgC: i 01; • ................; rvT ": &gt; v, &quot;" "v" ................ 'BFG - C (O) CH 2 NKSO 2 CH 3 -C (O) N (CH 3) z BFH-FC 2: 1% BFI- C (O) N (CH 3) 2;

I

·; &gt; 8BO $ ··; (Bgl-1) and Bgl-1 (Bgl-1). 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 / 8-O- 0> v v v!!!!!!!!!!!!!!!!!! C 8 UH₂ UN /O \0 U U U U U U U U U U U U U U U U U U U U U U U U U U U. 5 n: s v ^}. ^ wwww < -CH 2 - (O) N: CH 3, «J \ j | 'Λ Λ / / / / / / /'. / \ | BGf | C (O) NH2 Q -> (i.e. i. n. i; (i.e., in the presence of a compound of the formula: ## STR1 ## in which R 1 and R 2 are as defined in claim 1, 1, 2, 3, 4, 5, 6, 8, --------------------------------------------------------------------------------------------------------------------------------------------- OH), - - - - - - - - - 8 8 ': 0 - OH ·: ·: i, 0: 8 · ... 00 :. BHB-000: 8: 0: 00: 0, - * - -. 1-yl)

Ri:

BHC. Chb (CH 2) 3 H 3 Cl 3:

O

N-methyl-N-methyl-N- \ ./ v · '€' ··· &quot; N: / .γ

C-&quot; I ~ C ~~ H V * -s õ li / ¾ M j \\ <sJ \ V · ^ l Ò St / ¾ ^! ?! - ~ 0 ~ Η I! Vr &gt;: ___________! Eur-lex.europa.eu eur-lex.europa.eu

\ * £> v

The present invention further relates to compounds of general formula (Ic):

and pharmaceutically acceptable salts thereof, wherein, ¾¾ G, m, p and q are as defined above.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperazine Compounds of Formula (Ic) are those wherein G is H, and the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula general (Ic) A; those in which G is a

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of general formula (Ic) are those in which G is -L-D-DloDd .; and L represents a graft of the formula -C (O) &quot; .

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine dd compounds of formula (Ic) are those wherein G is -L-iCHgtXvONíd .; and L is -SO2- or -SO-.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein G is (C1-6) alkylene.

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine roms of formula (Ic) are those wherein G is -CH2 -R5.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is - (CH 2)

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is a group

In one embodiment, the 4-Tetrazolyl-4-compounds of the general formula (I) are those wherein G is - (-) -

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is a group of Formula

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is -L- (CH 2) nCi, and c is H.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is -L- (CH 2) 3, and R 4 is a C1 -C10 alkyl group

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is -L- and R &lt; represents a group -CH 2 O (alkyl j =

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is -L- (11), and R4 is a group of formula -CH2 NH (alkyl or (C1 -C10 alkyl),.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein G is a group of formula

Q 1 -C 4 COOR 4.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is a group

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is a group of the general formula

In one embodiment, the 4-Tetrazolyl-0-phenylpiperidine Compounds of formula: are those wherein G is -

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is -CS *;

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is -O-Gly;

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is -L1; R3 and R5 is a group of -NHSO 2 R 4.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula IIcj are those wherein G is -L- (CH 2) n R 2 and R 5 is a group- C (O) NHOH, -C (O) NH (C1-6 alkyl, -C (O) O) N

In one embodiment, the 4-phenylpiperidine compounds of general formula (Ic) are furthermore preferred in that the compound of Formula (L) is CF3; Sp & j-goqs-s (C1-C4 alkyl) or &quot;dv:; &quot;. In the embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is -CH 2 CH 2, and R 4 is a group of formula .

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is -L-CHain and L is -C ( W)".

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is -L- (CH 2) n R 5 β L is - SO2- or -S0-.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is - (C alquil alquil alquil) alkylene;

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein ρ is O.

In one embodiment, those of 4-tetrazolyl-4-phenylpiperidine of formula (Ic) are those in which p is I.

In one embodiment, the compounds 4-tetrazolyl-4-methylene glycine are those wherein p is 1 and the carbon region to which R 3 is linear is in a (R) configuration. of the general formula (Ic) are those in which p is 1 and the carbon atom to which R3 is attached is in a configuration (3).

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein p is 1 and R3 is -C1-3 alkyl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein p is 1 and R 3 is -CH 3.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein p is 1 and R 3 is C 1 -C 3 alkyl and the carbon atom to which R 3 is is in a (R) configuration.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (ic) are those wherein p is 1 and R 3 is -CH 3 and the carbon atom to which R 3 is is connected to a configuration (R).

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of general formula (Ic) are those wherein p is 1, R 3 is a group of the formula and the carbon atom is is in an (S) configuration.

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of the general formula (Ic) are those in which p is 1 and Fb is a group of the general formula and the carbon atom to which R3 is attached , will be in an (S) configuration.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein q is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein m is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein m is 1.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein m is 0 and p is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein m is 1 and p is 0,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein m is 0 and q is 4-Tetrazolyl-4- phenylpiperidine of general formula (Ic) are those wherein m is 1 and q is 0,

In the 4-tetrazolyl-4-phenylpiperidine compounds of formula (Ic) are those wherein a is C, p is 0 and q is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein m is 1, p is 0 and q is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein Iq: represents -Br, -Cl, -I or -F.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein R2 is -O (C1 -C3) alkyl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Tc) are those wherein R2 is a C1 -C6 alkyl group,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein 1 1 is -NH (C 1 -C 3 alkyl) or -N (C 1 -C 6 alkyl)

In one embodiment, the 4-Tetrazolyl-4-Fabbiphenylbib compounds of Formula (1e) are those in; which R3 represents -Br, -C ', -I or -F. In the context, the 4-tetrazolyl-4-phenylpiperidine compounds of general formula (Ic) are those wherein R 3 is -O (alkyl,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are O-O-OH wherein R3 is - (C1-4) alkyl,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (IC) are those wherein R 3 is -NH (C 1 -C 3 alkyl) or -N (C 1 -C 3 alkyl) 3 ,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein R 1 is H.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein Pi is -C (O) NH2, -C (O) NHOH, -C (O) 0) NH (alkyl or -C (O) N (C 1 -C 4 alkyl) a.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein the symbol (-) is -C (O)

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula represents a group of general formula

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of general formula (Ic) are those in which the symbol is -O (O) NHCH3. In general, the 4-tetrazolyl-4-phenylpiperidine compounds of general formula (Ic) are those in which the symbol "C (O) t" is a group.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine compounds of formula (Ic) are those wherein R 1 is -

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein R1 is -CHO.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein the D1 symbol is -CN.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein R &gt; represents a - (C1 -C6 alkyl) group.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein R1 is CN. N, N, N ', N', N ', N', N ' . i NL ·. D /

In one embodiment, the 4-Tetrazolyl-4-thiazole Compounds of Formula I; Â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ wherein Râ,, is 4-tetrazolyl-4-one, the phenylpiperidine compounds of general (Ic) are those in which R3 is a heteroaryl group (having 5 to 6 nucleotides)

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of formula (Ic) are those wherein Ar3 is substituted by one or more groups represented by R2.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is H and p is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is H and q is O.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is H and m is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ir) are those wherein G is H and m is 1.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine compounds of Formula (Ic) are those in; that G is H and H is a phenyl group.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine salts of Formula (Ic) are those wherein G is Η, p is 0 and c is 0.

In one embodiment, the compounds of formula (I) βipt :: 101.0,.:. ·. ·· &gt; (Ic) are those wherein G is H, H and p are 0 and m is 0.

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of formula (Ic) are those wherein G is Η, p is 0 and m is i.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is Η, p is 0 and Ar3 is phenyl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is Η, p is 0, q is 0, and m is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Ic) are those wherein G is a Mn of Η, p is 0, q is 0, and m is 1.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine compounds of general Formula (Ic) are those in which G represents a Î ±, Î ± -bis p represents 0, the 4-tetrazolyl-4-ferrylpyridine derivatives are those in which G is Η, p is 0, q is 0, and rr . represents 0 and the symbol Aj ··; represents a phenyl group.

On one .·. &quot; ... v

Illustrative phenylpiperidine compounds of general formula (Ic) structure: 4-tretazolyl-4-have the following

wherein the symbols G and R: are represented by the following:

, ί-νί · 1-. Eur-lex.europa.eu eur-lex.europa.eu Yes, ϊ ί Β Β 5 Β ΡΐΗ ΡΐΗ:

CAX: (CH2) 2: CH2) rC (O) NH2

AND EDITING

CBF: CH2) CH2 -C (O) C (O) MH2

CAZ -C: € Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α .......... 5 -'0 · Η · ϊ: Βό · ϊ Η ····································································································· -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 (CH 2) 2 - (CH 2) 2 - (CH 2) 3 - (CH 2) 2 - (CH 2) j

-C (O) NH2 ;;;;;;;;;;;;;;;;;;;; . Compound: Ho-, (1), (2), (3) and (4). · &Gt;:·; '·. (CBS i -CsO) (Cn) RotoO-ts, · '·; · &Gt; &gt;. *. The CBT! -CWQsCB j Λ W; CBC 1 ..Ο-η, ΟΟ- :, CBV; - - - - - - - - - - - - - (b) and (b), and (c) .................................. \ ... -; CSo - - - 0: 0-00: - ::: - ί -: 0 .-- :: 050,0: .0,0,0,0-: ......... .................. : | Ϊ Ϊ i i i i i i i i i i i i i i i i Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ. u, ...... ...... .............................. 1 CCB 'oO: δ: p, 0 ;:; ,  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ -CO-Cl-CCD j ----- CCCCsi, ν.ν. · Λντ ·. ·, Τν, ν.ν.ν.ν.ν .vvVVVW .............. ....... . ........... . . _s ! CCS | - CCCcss I 1 CCF | -Câ -C ¡C-HO &gt;; s-SG "".:; 'νϊ ·.! : ν '; ; . : ??????????????????????????????????????????? : L L í í í í í í-o C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - • C í í Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ ... ... ........ ........ ........ ........ ........ ........ ........ ........ ........ ......... Γ Γ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ , â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ C:-C:-C:-C:-C:-C:-C:-C:-C:-C:-C:-C:-C:-C :-

5

ccx

CHO CCY -H -I. Â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ , ¾ -CrfyC; d :; N H? C-h: &gt; (1), (2), (3) and (4) and (4) - - - - - - - - - - - - - - - - - - - : &quot; &quot; yyyy l: - C: i: CH-y-: dddddCn ·; - - 5 ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ; -cd | CDI-CCH-O-CN CD J - (CH>) ΥΫΦΒίΝ -CN \ CDK -> ν »-CN! .............. 1 CCL &quot; &quot; ...... 1 &quot; y .; γ. . Eur-lex.europa.eu eur-lex.europa.eu (2-methoxyphenyl) -1-piperazinecarboxamide; ·: &Lt; ^ ξ I ί .......... Ç'y &quot; : and «evavi ;; N, -; 1 'L-1'; : 0 'NRy i -CH3! CDT-CH 2 C (O) N (CH 3) 2 1 -ch 3 • .v.C; Eur-lex.europa.eu eur-lex.europa.eu j:;; In the preferred embodiment of the present invention, the present invention relates to a method for preparing a compound of formula (I). , and VC: V: CDW = CDX d ---. ¾: γ,; CDZ .............. [! Fig. CEà | (i.e. C0 ;; i jjdCCCH ·; f

\ 0 'o. Ο K K CE CE CE CE CE CE CE CE CE;;;;;;;;;;;;. ... nn \ W i X < ! 1). CCC CC 'IC-I3C CEG CH:> CcD: & &> BH iC jC jC''C'C CSC CSC CSC2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2C2CDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCDCD {SB-Ç § CEI-C ': IC ;; CH₂Cl₂: C₂ {H₂O: C22H₂O: C2 ;H₂O: 1 '-ch3 I CEK -H i 1: ΠΚ ϊ: - "i &quot;: í i" ;; Cr; CE ·; : (CH2) n C (O) N (CH3) 2 -C (O) NH (CH3) CEN -C; W: ; 0 &gt; -CH (O) NHCH 2 - (CH 2) s C (O) NH 2 -C (O) NH (CH 3) | ! (C) -C (O) NHCOC (O) NHCOCH (O): wherein: j CER -ch2co2ch3 -C (0) NH (CH3) \ __________________J &gt; &quot; iy .; ???????? CH 3 -C (O) NH (CH 3) 1 ????? EC! s ........... 1 f- CEO j! - - - - - - - - - - - - - - - - - CSC CviDiCeS 0 ESES ..... Λν Ϊ Çc E:}! ij: Γ · 51%: ν V V V V V V V V V V V V V V V V V V V V V V V V V Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ ! - (Cyclic) CsiCiC: C: 1 1 i ........... CCS j .........! ... --CSiSCsCBi ....... ..IC; (C 1 -C 6) -alkyl, -C (CH 2) 2, -C (CH 2) 2, -C (O) C H :CBrC: CF D ......... 1 l -H &quot; VC: v ,; E -3 :; s j ···· &lt; '·: ··: ·· - ··:: y ·; ·>. - Χ Χ Γ Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos Compos.

- C (O) N t CH :;

CFM

(1), (2), (2) and (4) and (4) and (4) -xxxxoso. tf. &lt; f &gt;

W / * 0 "N

0 &quot; U &quot; N)

• C-N

M / t-C-N 5 &gt; V · -; / • yy. -0 · -Η · -

: CI. -; ddttOvt 1 -CN .............................................. ي ................................................. ............................S..................... ................................ Cl C \ " C'pp; S? Ip? C? C? B? C? B? T? Fig. C &gt; JD &quot; . / ........ / | A,? / dd i J j Ο

The present invention further relates to the general formula (Id):

Η &quot; N &quot;, VCCvS &gt; ', V V.1. A &quot; and pharmaceutically acceptable salts thereof, wherein the solutions of the general formula (I) and (III) are as defined above. meanings defined above.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperazine Compounds of Formula (Id) are those wherein G is H,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of the general formula (Id) are those wherein G is -L-

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those in which G is -L- (CH 2) n C (O) OR 4 and L is a group of formula -C (O) -.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is -L- and L is -SO2- or -ONLY-,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is -L- and R4 is H.

In one embodiment, the 4-Tetrazolyl-4-G-Compounds are a group of the formula: and R 2 is C 1-6 alkyl,

C 1 -C 4 -alkylphenylpiperidine of formula (1) are those wherein G is -L- (Clp) X, ClHIII and R4 is -O10.0 (CH3) ;O ·

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is -L-HYBRIDYLOCH1 and 0: 1 is C 1 -C 4 alkyl) or -C (O): 3 (C 1 -C 4 alkyl)

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is - (

C 1 -C 5) COOR 4.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is a group of the general formula

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein G is -H-1H-}.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein &lt; RTI ID = 0.0 &gt; that G is a group of formula

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of the general formula ## STR1 ## in which G is a group of the general formula -> 1¾ · r-COCbq,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compound of Formula: are those in which G represents a group of formula

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is a group of the formula and R 5 is -NHSO 2 R 4.

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds and the general formula (Id) are those wherein G is -L- (CH 2) n R 5 and R 5 is a group of the formula -C (O) NH (C 1 -C 4 alkyl) or -C (O) N (C 1 -C 4 alkyl) 2

In one embodiment, the Î ± 4-tetrazolyl-4-phenylpiperidine compounds of the general formula (Id) are those wherein G is -L- (CH2) nR5 and R5 is -CH2- SO 2 NH 2, -SO 2 NH (C 1 -C 4 alkyl) or -SO 2 N (alkyl) 2

In one embodiment, the general 4-Tetrazolyl-4-phenylpiperidine Compound (Id) compounds are those wherein G is a group of the general formula and R 5 is -CHbbOgB :,

In one embodiment, the 4-Tetrazoyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein L is a group of the formula: L is -C (O) -. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is a group of the formula and odioxolopropoery; .u :: · rdoo group. ·.; ..:.; srrvi 1 ···· ·.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is -O- (alkylene).

In one embodiment, the 4-Tetrazolyl-4-

phenylpiperidine derivatives of the general formula (Id) are those in which G is -V

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is - (CH 2)

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those in which the

G represents a group of the general formula &quot; dCllP

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is -

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of general formula: Td: are 0000. 00 wherein G is the group of the general formula ## STR5 ## in which the The compounds of formula (I) are those of formula (I): wherein R1, R2 and R3 are as defined above.

In one embodiment, the phenylpiperidine compounds of formula (Id) are those wherein p is 1.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine derivatives of formula (Id) are those wherein p is I and the carbon atom to which E is attached is in an R 1 configuration.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein p is i and the EtOEib carbon to which R3 is attached is in an (S) configuration.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein p is 1 and 0: C 1 -C 4 alkyl

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein p is 1 and R 3 is -CH 3.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein p is 1 and R 3 is C 1 -C 3 alkyl and the carbon atom to which R 3 is the 4-tetraazolidine-4-phenylpiperidine compounds of Formula (Id) are those wherein p is 1 and R3 is a group of general formula -CH3 and the carbon atom to which the symbol is attached is in a configuration (R). Phenylpiperidine of the general formula (Id.) Are those in which p is 1 and F :; represents a Ciovoyl alkyl group and the carbon atom to which the symbol% is attached is in a (E) configuration.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein p is 1 and R3 is -CH3 and the carbon atom to which R3 is attached is in a configuration (ti>

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein q is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein m is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein m is 1.

In one embodiment, the 4-methacryloyl-4-phenylpiperidine compounds of the formula: (Id) are those wherein m is 6 and p is 0.

In one embodiment, the 4-Tetrazolyl-4-General Compound (Id); â € ƒâ € ƒâ € ƒwherein m is 1 and p is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of the general formula are those wherein m is 0 and q is 0,

In one embodiment, the 4-tetrazolyl-4-oilyloylureido compounds of the general formula are those wherein m is 1 and q is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein m is 0, p is 0 and q is 3.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein m is 1, p is 0 and q is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein R 1 is -Br, -Cl, -I or -S

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein R2 is -O (C1-6 alkyl,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein Rz is a framework-alkyl group, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those in which the rhodioid R 2 represents a group -NH (

In one embodiment, the 4-tetrazolyl-4-phenylpiperazine derivatives of the general formula (II) in which F 1 is O-t-Br, -Cl, -I or -r.

In one embodiment, the utoratol-4-phenylpiperidine compounds of formula (Id) are those wherein R3 is -O-

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein Bc is -C1-4 alkyl,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein Ra is -NH (C 1 -C 6 alkyl) or -N (C 1 -C 3 alkyl) 5 ; ,,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id.) Are those wherein R 1 is H.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein R1 is a group of the formula -C (O) NH2, -C (O) NHOH, -C (O ) NH (C1 -C4 alkyl) or -CN, (C1-4 alkyl)

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein R1 is -C (O) N (

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those in which the symbol represents a group of formula (D

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine compounds of the general formula (Id) are those wherein: represents a group of the formula -C (O)

In one embodiment, the compounds of formula (I) are those wherein R1 is a group of formula C; 0; N,

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein; represents a group -COOR 4.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein E; is -CHO.

In one embodiment, the 4-Tetrazolyl-4-phenylpipericycin Compounds of Formula (Id) are those wherein R1 is -CN.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein R 1 is - (C 1 -C 4) alkyl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein R 4; represents a group of general formula

In one embodiment, the 4-tetrazolyl-4-phenylpiperidine compounds of formula (Id) are those wherein: R1 is phenyl, naphthyl, anthryl or phenanthryl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine compounds of general formula (Id) are those wherein the symbol represents a heteroaryl of 1-5 to 7 atoms in the nucleus).

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein ΆΓ3 is substituted by one or more groups represented by Ra-

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is H and p is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is H and q is O.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is H and m is

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine isopropyl ethers of general formula; Id; are those in which G represents Η or im: imboi.q m represents -

In one embodiment, the 4-t-, 11-4-phenylpiperidine compounds of Formula 1 are those wherein G is H and H is phenyl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (1d) are those wherein G is Η, p is 0 and q is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is Η, p is 0 and m is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is Η, p is 0 and m is 1.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is Η, p is 0 and Ar3 is phenyl.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is Η, p is 0, O is 0 and C is 0.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is Η, ρ is 0, q is 0, and m is 1.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is H, p is 0, q is 0, and the symbol is a phenyl group.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of Formula (Id) are those wherein G is an a and Η atom, p is 0, q is 0, m is 0 and Ar represents a phenol group.

Illustrative compounds of 4-tretazolyl-4-phenylpiperidine of the general formula (Id) have the following structure:

and pharmaceutically acceptable salts thereof, wherein G and T are represented by the following:

ix .......... &quot; C DAT -H -C (O) NH2 r ·· - ··· .................... . ................................................. D .................................. 1 DAU -TCTJC ÇCC BíÇí -c ÍJJHz qu W W WHzHzHzHzHzHz & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & (0) NH2 i DAY - BCN-iCiiC TCC B CCBVi, D \ - DAZ - C (O) (CH3) ABaSiCi -C (O) NH2. ;! Hahahaha DBB -C (O) NH2 DBE ~ (CH3) vCTCCB: '; -C (O) NH 2

DBF DBG

(C 2 -C 4) alkoxycarbonyl (C 1 -C 4) alkyl, (C 1 -C 4) alkyl, : tb______________________________________ tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb - - - - - - - - - - - - - - - - - - - - - - - - - - (CDClâ,ƒ): â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ - (CH2) n-NCH2), - (CH2) n - CN "OCCCND DCB -ch2so2nh2 -CO2CH3! .................. DCC .................. 1 ... ................................. ÍH3T2 ......... ....... ...... ™ C2ChT ............ \ 1 DVD - ΟαΗ CNNIS0; -N "OCpCH ;; ............. í | I D CE &quot; (I.e. The reaction mixture is filtered and the filtrate is evaporated to dryness. COCO ..... â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ1 -CHO (CH2) -CHO: j -CHO ........... 1! :  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ  € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ 1 ............................................ 1 -CHO v ' O'! : &Lt; / RTI &gt; CH: n3, CH3, CH3, CH3. i hollow: i &quot;coo;: CCC j &quot;OCOO;00-; ΟΗ &gt; "C HO j -: O: ίΝίΏχΝΝ-ΝΝ:

l DE: c '· · p \ ύ ·. : Wherein: R 1 is hydrogen; Fig. \ IX * \ and j DEI "i ν '. ; : &numsp; &numsp; &numsp; &numsp; &numsp; &numsp; &numsp; &numsp; DEK -H 1 -C (O) NH (CH 3) -C (O) NH (CH 3) I ..... DEN .......................................................................................................... ..................... .................................... '1 ______________________________________..._____...________________________________ ^ __________________________________________________ &lt;! :  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (O) NH (CH 3) 1 ν ... v ............................. ............. i DER &quot; CHyCy-EJHs ~ c gb bh sGéu \ |) |; s ...... | (1) NH (CH3) | DEV j 1 or x: yy -UiWiHH j DEW-CCIM and CGSIGIG-C (0) 0) NH (CH3) i DEX-CH2 CH2 CH3 -CH3)

j '|) |; γ i' -EgE | DEC · ''%! &gt; (I.e. : v ·· ¥ -:. ·:; ·, ·! ·>. i-G4: &lt; / RTI &gt;G-D; UIBBEEB j-C; In addition, the present invention relates to the use of the term &quot; BBC &quot; È: &gt; G ·,:; Εν; G-f:; &quot; : E G; G; V-; 5; v; j h E CI; W ·; C &gt; \ s í} ;; and f and y j> DFP DFR DFS &quot; dft &quot;

(CH 3) 2-C (O) N (CH 3) 2-C (O)

(3H, s), 7.9 (1H, t,

DFX (0) NH2

DFY -CH2C &lt; 0) N (CH3) 2 - (O) - (O)

'/ / / / / / / / / / / / / / / / / / / / / / / / / / / /. Ν 0 ίΐ | / \ Μ Ur \ / • ';;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; .................... 4 ~~ 4 Ν ···· ο% \ ....... / Ο

V ~ ΟΗΗ s \ wCH ^ \ ___ / ο ....................................... &quot; is &quot; N-Shh &quot; I / OWWW η \ Μ Μ Μ Μ Μ Μ Μ .... .... .... .... .... .... .... .... .... .... .... /

-G-N / -: - -! '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' .....; ::; j. Eur-lex.europa.eu eur-lex.europa.eu u / '- &quot; Λ' -c-N) · ::::! - ϊ ϊ ϊ ϊ ϊ ¾ ¾ ¾ ¾ ¾ ¾. A W Λ \ »Λ \ * Λ * ^. M / e)

j

Compound No. 1. 1 Ρ · ι 'o i D I K: no. I-C-N P i ....... / f A! -r->:! A compound according to any one of claims 1 to 4, wherein: . d: &gt; ' Y -CN pi \ / 'j DIU ...................................... ... I ................ DI DIW - | ;; : DIY DIY DIY __________________________________________________________ DIY DIY -----------------... ...... -CN HYDROCHLORIDE; (I) and (I) and (I) and (C) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 10, 10, 10, 10, 10, 4.3 Processes for Production of 4-Tetrazolyl-4-Phenylpiperidine Compounds, Processes for the Production of 4-Tetrazolyl-4-Phenylpiperidine Compounds, 4-Tetrazolyl-4-Phenylpiperidine Compounds

The 4-Tetrazolyl-4-phenylpiperidine Compounds of the present invention can be prepared by conventional organic syntheses and by the following methods: Scheme I describes processes for the production of · · R mobile phone ρ 0 ·.!.! - 14 &quot; Wherein ρ X is -C (O) NZ2, wherein each mm: d and Z are as defined above. alkyl group or both groups and the nitrogen atom to which they are attached are taken together to form N-4-Rd aziridyl, azidoidyl, pyrrolidyl, piperidyl, homopiperidyl, pyrrolyl or morpholinyl. of bromine 1 are converted to the bromine acid chlorides 2 using thionyl chlorides (JS Pizey, Synthetic Reactions 2: 65 (1974).) The bromine acid chlorides 2 are reacted with O 10, optionally in the presence of a base such as, to give the reactive intermediates 3 which are treated with 4-cyano-4-phenylpiperidines 4 (scheme 10) to give the cyanophenyl compounds 5. The cyanophenyl compounds 5 are treated with MesSnhd or Me 3 SiN 3 and tin oxide (SJ Wittenberg et al., J. Org. Chem., 5, 8, 4134-4141 (1993)) to provide 4-Tetrazolyl-4-phenylpiperidine compounds 6, wherein O is a group Compounds 6 are reacted with Gi-X, in which G1 is all G, defined above, except hydrogen, and X is a leaving group such as halogen, sulfonate, methanesulfonate or trifluoromethane toluene sulfonate groups to give a The mixture of the 4-Tetrazolyl-4-phenylpiperidine Compounds 7 and 8. The 7 and 8 are separable using conventional means, such as, silica gel chromatography, high performance liquid chromatography can be obtained

C 1 -C 10 alkyls form or are produced using organic synthesis processes

Scheme 11, Scheme 1, and Scheme 1, Scheme 1, Scheme 1, Scheme 1, Scheme 1, Scheme 1, S

wherein R 2 and R 3 have the meanings given above, and -W- represents a group of the general formula -O-oxoxy groups; - 00 Hi Uij i'fe b -. Scheme 2 describes processes for the production of compounds of formula (I) wherein the symbol is -CO2 R4. The bromine acid chlorides 2 (Scheme 1) are reacted with the presence of a base, pyridine, 4-triethylamine or sodium bicarbonate. The bromo esters 9 are reacted with 4-cyano-4-phenylpiperidine 4 (scheme 10) 1, which yields the cyanophenyl compounds 10, which are treated tb: bqbb or bbqbbibb and tin oxide (SJ Wittberg et al., J. Org. Chem., 5, 33: 4139-4141 (1993)) to provide the 4-Tetrazolyl Compounds -4-phenylpiperidine 11, wherein E 1 is G and R 2 is H. Compounds 11 are reacted with G1-X, wherein G% and X are as defined above to provide a mixture of the 4-Tetrazolyl-4-phenylpiperidine Compounds 12 and 13. Compounds 12 and 13 are separable using the conventional means described above.

Scheme 2 g-t

in which m, p, q, Es, and% are as defined above, and -W- is -C (Ar) (Ara) - or -Y1R) (Ars) -. Scheme 3 shows processes for the production of compounds of which the symbol

R1 represents a group of formula

Ci). Compounds 11 (scheme 2) are protected with a stable protecting group of bases, such as mesitylene sulfonamide groups; cyclohexanecarboxylate; I- &quot; dis-edd 1-2-2: 1-N-α-acetates: ethyl; in a similar protecting group (See, TW Greene et al., Protective Groups in Organic Synthesis 615-631 (ISMH) to provide the protected compounds 14. Compounds 14 are hydrolyzed using the hydroxide as the base, optionally in the presence of After treatment, the title compounds are obtained, which are amidated using Compound 16 to provide the protected compounds. Compounds 16 are deprotected using a strong acid (Greene at 615-631 , to give the 4-Tetrazolyl-4-phenylpiperidine compounds 17, wherein R 1 is C (O) NH (C 1 -C 4 alkyl) and G is H. Compounds 17 react with Gi-X, wherein G 1 and X are as defined above, to provide a mixture of 4-Tetrazolyl-4-phenylpiperidine Compounds 18 and 19. Compounds 18 and 19 are separable using conventional means described above.

Scheme 3

iA ....... d 7: H group of / \ 5x

.....; (X): - (X) - (X) - (X) '/

X &quot; ------- * "% / - &quot; . m i il · X \> c 'ΐ {** ·, $ ----

X ίί>. 17

Wherein R 1, p, q, R 2 and R 3 are as defined above and -W- is -C (Ar) aryl- or -C (H The compounds 15 (Scheme 3) are known to form a compound of the formula: ## STR1 ## in which the compound of formula (I) is a compound of formula (I). Protected compounds 20 are obtained which are deprotected using strong acid (Greene et al., to give the compounds of 21, wherein R1 is -C (O) ) CH 2 OH and G is H. Compounds 21 are reacted with G1-X, wherein G1 and X are as defined above, to give a mixture of the compounds of 1-R &lt; 1 1-M-phenylpiperidine 22 and 23. Compounds 22 and 23 are separable using the conventional means described above.

Scheme 4

in which m, p, q, H are symbols. and R 3 are as defined above and the symbol represents a -C (Ar) Ar (Ar 2) - or -C (d 1 Ar 3) group. Scheme 5 describes processes for the production of 4-Tetrazolyl-4 -phenylpiperidine, in which R4 is CH3. The bromides 24 are treated with 4-cyano-4-phenylpiperidine 4, to provide the intermediates of Scheme 25, which react with chloroform; cm and tin oxide (SJ Wittenberg et al., J. Org. Chem., 5B: 4139-4141) to provide the 4-

&quot; wherein R 1 and G are H atoms. Compounds 26 react with Gi-X, wherein G 1 and X are as defined above, to give a mixture of the compounds ae 4-tetrazolyl-4-phenylpiperidine 27 and 28. Compounds 27 and 28 are separable using the conventional means described above. 4. Scheme 5

H3SnN3

defined above and - W- represents a group of x ·: fcd '·; <1' C (Ari) or -Cf for the production of Hm. in which Scheme 6 describes 4-tetraalkyl 1-4 compounds is -CHO. The 4-Tetrazolyl-4-phenylpiperidine Compounds 27 (Scheme 5) are treated with a strong base such as, Î »1: λ 7: and the reaction is quenched with dimethylformamide (see, U. S. et al., Syntel., 975 (1994)) to provide, after workup, the protected aldehydes 28. Protected aldehydes Greene, 615-6311, to provide the compounds of 4-Tetrazolyl-4-phenylpiperidine 29, wherein Î'is -CHO and G is H. compounds 29 are reacted with Gi-X, wherein Gi and X are as defined above, to provide a mixture of the 4-Tetrazolyl-4-phenylpiperidine Compounds 30 and 31 which are separable using the conventional means described above.

Scheme 6

The? in which m, p, q, R2 and ii are as defined above and -W- is -C (Ar) (Ar2) - or -C (H) (Ar3) -. Scheme 7 describes processes for the production of 4-Tetrazolyl-4-phenylpiperidine compounds, wherein K; represents a group of C1-6alkyl. Compounds 27 (scheme 5) are treated with such a strong base, such as, for example, by filtration and evaporation. wherein X is as defined above, to provide the protected compounds 32. Compounds 32 are deprotected from chlorotides 615-631) to give the 4-Tetrazolyl-4-phenylpiperidine compounds 33, in which SiMY &apos; is a - (C1-3 alkyl, and G represents a compound of the formula: ## STR10 ## in which G is as defined above, to give the 4-Tetrazolyl-4-phenylpiperidine compounds 34 are separable using the conventional means of H. The i and X's have the mixture e 35, which described 7

Scheme

Wherein m, p, q, f and e are as defined above and -W- is -C (Ar) (Ara) - or -C (H) (Ara) -. Scheme 8 describes processes for the preparation of &quot; (Scheme 3) are treated with NH 4 (see, MB Smith et al., J. Org. And to provide protected amides which are deprotected (Greene at 615-6311) to provide compounds of the general formula (I). -tetrazolyl-4-phenylpiperidine 37, wherein G = -ORG® is the general formula -OGG®: and G is a GH atom. Compounds 37 react with GtX, wherein Gi and X are as defined to provide a mixture of the 4-Tetrazolyl-4-phenylpiperidine Compounds 38 and 39 which are separable using the conventional means described above.

Scheme 8

P . Gt; &lt; / RTI &gt; &lt; / RTI &gt; m. b mt 1% G

G-Xy

Wherein R 1, R 2 and R 3 are as defined above, and -W- is -C (O): M 5 5 (Ar 2) - or -> Scheme 9 describes processes for the production of 4-Tetrazolyl-4-phenylpiperidine compounds, wherein Fx is -CN. D.r 4-Tetrazolyl-4-phenylpiperidine Compounds 37 (Scheme 8) are treated with Hâ,,S and CCâ,ƒâ, {W.J. Rogers, Synthesis 41 to obtain the 4-Tetrazolyl-4-phenylpiperidine Compounds 40, wherein Ex is -GN and G is H. Compounds 40 react with Gi-X, wherein Gi and X are as defined above, to provide a mixture of the 4-Tetrazolyl-4-phenylpiperidine Compounds 41 and 42, which are separable using the conventional means described above.

Wherein m, p, q, R2 and R3 are as defined above, and -W- is a group of benzyl; ? Aoo-devi; (Ar3) -. Scheme 10 describes ptomeurto® for the preparation of the 4-cyano-4-phenylpiperidines. The aminodiols 43 substituted in 01.0 are N-alkylated using benzyl chloride 44, in order to obtain the N-benzyl 45 diols , which are colored using CH 2 Cl 2 to give the dichorides 46. The dichlorides 46 are condensed with deprotonated benzyl cyanides 47 in toluene) to give the benzyl compounds 48, which are debenzylated using H 2 and Pd / C (EtoH at 95 ° C) to give the 4-cyano-4-phenylpiperidines 4.

PM

Scheme 10 <1S5

2, benzyl chloride (44)

ίΐί 4

Some 4-Tetrazolyl-4-phenylpiperidine compounds may have asymmetric centers and therefore exist in the different enantiomeric and diastereomeric forms. A compound of 4-Izairaeryl ···! May be in the form of an optical isomer or a diastereomer. Accordingly, the present invention encompasses 4-tetrazolyl-4-phenylpiperidine compounds and their derivatives as described hereinbefore in the form of individual optical isomers, diastereomers and mixtures thereof, including a racemic mdnitris .

ItléS; Furthermore, certain α-4-tetrazolyl-4-phenylpiperidine compounds may exist as tautomers. For example, when G is H, some 4-tetrazolyl-4-phenylpiperidine compounds of general formula (Ia) and general formula (Ib) (for example the AAT and BAT structures) and certain compounds of 4 (Ic) and of general formula (Id) (for example, the CAT and DAT structures) are tautomers of one another. Each structure described herein is intended to encompass all of its tautomeric forms, each of which is understood to be induced in the present invention, whether specifically written or not and whether or not the tautomers described herein represent an excess tautomer relative to any other tautomer. Accordingly, the present invention also encompasses the 4-Tetrazolyl-4-phenylpiperidine Compounds and their uses, as described herein in the form of their individual tautomers.

In addition, one or more hydrogen, carbon or other atoms of a 4-tetrazolyl-4-phenylpiperidine compound may be unsubstituted by an isotope of hydrogen, carbon, or other atoms. Such compounds, which are encompassed by the present invention, are useful as diagnostic tools and tools in metabolism pharmacokinetic studies and growth assays. 4.4 Therapeutic Uses of 4-Tetrazolyl-

According to the present invention, the 4-Tetrazolyl-4-phenylpiperidine Compounds are administered to an animal, in a mammalian, in another embodiment, a human, for the treatment or prevention of pain. The 4-Tetrazolyl-4-phenylpiperidine Compounds can be used to treat or prevent acute or chronic pain. For example, the 4-Tetrazolyl-4-phenylpiperidine Compounds may be used for, but not limited to, the treatment or prevention of cancer pain, central pain, labor pain, myocardial infarction pain, pancreatic pain, pain colic, postoperative pain, headache, muscle pain and pain associated with intensive care.

The 4-Tetrazolyl-4-phenylpiperidine Compounds may also be used for the inhibition, prevention or treatment of pain associated with inflammation or an inflammatory disease in an animal. Pain to be inhibited, treated or prevented may be associated with inflammation associated with an inflammatory disease, which may appear when there is inflammation of the body tissue and which may be a local inflammatory response and / or systemic inflammation. For example, the 4-Tetrazolyl-4-phenylpiperidine Compounds may be used to inhibit, treat or prevent pain associated with inflammatory diseases including, but not limited to: organ transplant rejection; re-oxygenation traumas resulting from organ transplantation (see, Grupp et al., J. Mol. Cell Cardiol. 31: 297-303) including, but not limited to, transplantation of the heart, lung, liver or kidney; inflammatory diseases arthritis, osteoarthritis, and bone diseases associated with increased bone resorption, inflammatory bowel diseases such as ileitis, colitis, Barrett's syndrome, and Crohn's disease; lung diseases such as asthma, stress g-ssp &amp; tt &lt; t &gt; s syndrome and chronic obstructive airways diseases; inflammatory eye diseases, including corneal dystrophy, trachoma, haemolytic, sympathetic ophthalmitis and endophthalmitis; gum disease including gingivitis and periodontitis, tuberculosis, leprosy, inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and nephiosis; inflammatory diseases of the skin, including scleroderma, psoriasis and eczema; inflammatory diseases of the central nervous system, including diseases of chronic nervous system demyelination, multiple sclerosis, AIDS-related neurodegenerative disease and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral encephalitis or autoimmune disease; autoimmune diseases, including type I and type II diabetes mellitus; diabetic complications, including but not limited to diabetic cataracts, glaucoma, retinopathy, nephropathy (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, mononeuropathy, autonomic neuropathy, gangrene of the feet, atherosclerotic coronary artery disease, peripheral arterial diseases, non-ketonic hyperglycemic hyperosmolar coma, foot ulcers, joint problems, and a complication of the skin or mucous membrane in the. such as an infection, a spot on the cinnamon, a candida infection or a necrotic lipoid necrobiosis diabeticorum); Immune complex vascuitis, systemic lupus erythematosus UMB) n inflammatory diseases of the heart, such as, cardiomyopathy, hypercholesterolemia of ischemic heart disease and atherosclerosis; as well as other diseases which may have significant inflammatory components, liver enzymes, including preeclampsia, chronic brain and spinal cord insufficiency, and cancer. The 4-Tetrazolyl-4-phenylpiperidine Compounds may be used to treat or be associated with inflammatory diseases which may, for example, be a systemic inflammation of the body , exemplified by gran positive or grani negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to proinflammatory cytokines, e.g., shock associated with proinflammatory cytokines. Such shock may be induced, for example, by a chemotherapeutic agent which is administered as a treatment for cancer.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds are administered to an animal, in one embodiment, to a mammal. In another embodiment, a human being for the treatment or prevention of diarrhea. The 4-Tetrazolyl-4-phenylpiperidine Compounds can be used to treat or prevent acute or chronic diarrhea. For example, the 4-Tetrazolyl-4-phenylpiperidine Compounds may be used, but not limited to, treating or preventing acute diarrhea caused by a virus, such as, but not limited to, Norwalk virus, Norwalk-like virus , rotavirus and cytomegalovirus: protozoa, such as, but not limited to, Girardia lamella,

Crpytosporidium and Entamoeban histolytica; and bacteria, including but not limited to Staphylococcus aureus, Bacillus cereus, Clostridium perfringens, enterotoxigenic E. coli, E. coli, E. coli L.,

MppçEçy Yibrio ρ ·· ί o bm-w:; pyrite. Clostridium Salmonella, entero-invasive E. coli,

Aeromonas, PI is iomonas, Yersinia Ai / ooyb ·, q;

Nisseria and hysteria monocytogenes. For example, the compounds of 1: 1-.beta. Theophylline may be used for the treatment or prevention of chronic diarrhea classified as including, but not limited to, osmotic diarrhea, secretory diarrhea or resulting from an inflammatory condition, a syndrome of a motile disorder and a chronic infidelity. Applicants believe that unlike traditional opioid agonists and non-steroidal anti-inflammatory agents, the 4-tetrazolyl-4-phenylpiperidine compounds do not significantly cross the blood brain barrier. Accordingly, Applicants believe that administering an effective amount of a 4-Tetrazolyl-4-phenylpiperidine Compound to an animal results in fewer side effects, including respiratory depression, unwanted euphoria, sedation, constipation, increased tolerance to the drug and increased dependence on the drug, which may result from the administration of traditional opioid agonists or non-steroidal anti-inflammatory agents. In one embodiment, administering an effective amount of a 4-Tetrazolyl-4-phenylpiperidine Compound to an animal does not result in any of the side effects mentioned above. Therefore, in certain embodiments, the methods of the present invention encompass the treatment or prevention of pain, while reducing or eliminating one or more of the above-mentioned side effects.

Without being bound to a theory, it is believed that the 4-Tetrazolyl-4-phenylpiperidine Compounds are agonists and accordingly are capable of stimulating a receptor of the present invention. wherein said cell is capable of expressing an opioid receptor with an effective amount of a 4-Tetrazolyl-4-phenylpiperidine compound. The process is also useful for the stimulation of opioid receptor function in an in vitro cell. In an animal, a subject is contacted by a cell capable of expressing an opioid receptor, with an animal, with an effective amount of a 4,4-tetrazolyl-4-phenylpiperidine. In one embodiment, the method is useful for treating or preventing pain or diarrhea in an animal. Brain tissue, spinal cord tissue, immune cells, gastrointestinal tract cells and primary nerve cells are examples of tissues and / or cells which are capable of expressing an opioid receptor. This process can be used in vitro, for example as an assay to select cells expressing an opioid receptor. 4.4.1 Therapeutic / Prophylactic Administration and Compositions of the Present Invention

Due to their activity, the 4-Tetrazolyl-4-phenylpiperidine Compounds are useful, advantageously, in veterinary medicine and in humans. As described above, the 4-Tetrazolyl-4-phenylpiperidine Compounds are useful for the treatment or prevention of pain or diarrhea in an animal in need thereof.

When administered to an animal, the 4-Tetrazolyl-4-phenylpiperidine Compounds can be administered as a component of a pharmaceutical composition, which comprises a carrier. acceptable excipient is safe from the pharmaceutical point of view. The present compositions, which comprise a rM compound are, in one embodiment, administered orally. The compositions &quot; the present invention may also be administered by any other convenient route, for example, by infusion or injection of the bolus, by absorption through the epithelial or mucocutaneous lines (e.g., oral, rectal and intestinal mucosa, etc.) and may be administered together with any other therapeutic agent, ketone may be systemic or local. Various delivery systems are known, for example, encapsulation in liposomes, microparticles, microcapsules, ethoxide, etc. and may be used to administer the 4-Tetrazolyl-4-phenylpiperidine Compounds.

Administration methods include, but are not limited to, intradermal, intramuscular, intrapertonal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, inhalation, or topical administration, particularly in the ears, nose , eyes or skin. The mode of administration is left to the physician's description. In most cases, administration will result in the release of 4-Tetrazolyl-4-phenylpiperidine Compounds into the bloodstream.

In specific embodiments, it may be desirable to administer the 4-Tetrazolyl-4-phenylpiperidine compounds locally. This can be achieved, for example, although not considering as a limitation, by surgery during the local infusion, topical application, for example, together with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or by means of an implant, said implant being a porous, nonporous or gelatinous material, including membranes, such as sialastic membranes or fibers.

Pulmonary administration may be used, for example, by using the inhaler in the form of a nebulizer; aerosolization or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, those of 4-tetrazolyl-4-phenylpiperidine may be formulated as a suppository with conventional binders and excipients such as triglycerides.

In another embodiment, the 4-Tetrazolyl-4-Phenylpiperidine Compounds may contain: released into a vesicle. In particular, a liposome (see, Langer, Science ZaR: 1527-1533 (1990) and Treat et al., Liposomes in the Therapy of Infectious Dyssease and Cancer 317-327 and 353-365 (1989).

In yet another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds can be released in a controlled release system (see, for example, Gocdson, in

Medications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled release systems described in the review by Langer, Science 2.4.9 .: 1527-1533 (1990), may be used. In one embodiment, a pump may be used (Langer, Science 2.43 .: 1527-1533 (1990);

Sefton, CRC Crit. Biomed Ref. Eng. 1.4: 201 (1987); Buchwald et al., Surgery S.8: 507 (1980); and Saudek et al., N. Engl. J. Med., 321: 574 (1989)). In another embodiment, polymeric materials may be used (see, Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled

Drug Bioavailabiiity, Drug Product Design and Performance (Smolen and Bali eds., 1984); Ranger and Peppas, J. Macromol. Know. Rev. Macromol. Chem. .2.3: 61 (1983); Levy et al., Science 228: 190 (1985); During et al., Ann. et al., 25: 351 (1989); and Howard et al., J.Buyscpff., Pl: 105 (1989)). While still in the framework, a controlled release system may be placed in the vicinity of a target of one; of 4-tetrazolyl-4-phenylpiperidine, only a fraction of the systemic dose was required.

The present compositions may optionally comprise an appropriate amount of a pharmaceutically acceptable excipient in order to provide the appropriate dosage form for the animal.

Such pharmaceutical excipients may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut butter, soybean oil, mineral oil, sesame oil and the like. Pharmaceutical excipients may be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. When administered to an animal, the pharmaceutically acceptable excipients may be sterilized. Water is a particularly useful excipient when the 4-tetrazolyl-4-phenylpiperidine compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be used as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol and the like. The present compositions, if desired, may also contain minor amounts of wetting agents or emulsifiers or pH buffering agents.

Suitable carriers or excipients are, for example, pharmaceutically acceptable carriers, for use in the manufacture of pharmaceutically acceptable excipients. venous compounds of the 4-Tetrazolyl-4-phenylpiperidine Compounds include, but are not limited to, solutions

water from about 25 to about 30% and normal saline (about 0.9%),

O . 30

Pharmaceutically acceptable carriers or excipients suitable for intraperitoneal administration of the 4-Tetrazolyl-4-phenylpiperidine Compounds include, but are not limited to, normal saline (about 0.9%), PEG diluted with a saline solution or water of about 25 to about 35, propylene glycol (PG) diluted with 25 to about 30% saline or water and hydroxylpropyl-β-cyclodextrin diluted with water of about 2 to about 30%.

Suitable and pharmaceutically acceptable carriers or excipients for subcutaneous and intramuscular administration of 4-Tetrazolyl-4-phenylpiperidine Compounds include, but are not limited to, normal saline (about 0.9%), , PEG diluted with a saline solution or water of about 25 to about 30% and PG diluted with saline or water of 25 to about 30%.

Pharmaceutically acceptable carriers or excipients suitable for oral administration of the 4-Tetrazolyl-4-phenylpiperidine Compounds include, but are not limited to, normal saline (about 0.9 polyethylene glycol and Su diluted with a saline solution or water of about 25 to about 36%, hydroxypropyl-β-cyclodextrin diluted with water of about 2 to about 30%, dilute PG: a saline or water of 25 to about 5%.

Pharmaceutically acceptable carriers or excipients suitable for intracerebroventricular and intrathecal administration of the 4-tetrazolyl-4-phenylpiperidine compounds and the like, οο-οορίο; normal saline (about 0.9%),

The present compositions may be in the form of solutions, suspensions, tablets, dragees, granules, capsules, capsules containing liquids, powders, sustained release formulations, suppositories, aerosols, sprays, suspensions or any other form suitable for use. In one embodiment, the composition is in the form of an eapsulin (see, for example, U.S. Patent No. 5,698,155). Further examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R.

Gennaro ed., 19th ed. 1995), incorporated herein by reference.

In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds are formulated according to routine procedures as a composition adapted for oral administration to an animal, particularly a human. Oral delivery compositions may be in the form of tablets, dragees, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs, for example. Orally administered compositions may contain preservatives, coloring agents, and the like; or more agents, for example, sweetening agents such as fructose, aspartame or saccharin, and flavoring agents such as peppermint, gallant oil or chorizo. for powder. A pharmaceutical preparation having the formula. In addition, when in the form of compositions, they may be odorless to retard the treatment and thus provide a sustained release over an extended period of time. Membranes selectively surrounding a subject compound are also suitable for orally administered compositions. In these latter platforms, the ambient fluid surrounding the capsule is soaked in the main compound, which increases in volume to displace the agent and causes agents to form through an aperture. These hybrid platforms can provide a release profile of practically the order 0 as opposed to the profiles of the Immediate Release formulations. A time delay material such as glycerol monostearate or glycerol stearate may be used. Oral compositions may include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose and magnesium carbonate. In one embodiment, such excipients have a pharmaceutical grade.

In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds can be formulated for intravenous administration. In one embodiment, the compositions for intravenous administration comprise the compound dissolved in a sterile, isotonic, aqueous buffer. When necessary, the compositions may include solubilizing agent.

The intravenous compositions may optionally include a local anesthetic such as lignocaine to decrease pain at the site of injection. Generally, the ingredients given separately in admixture are in the form of an aqueous solution, eg, as lyophilized anhydrous powder, an Igld: free concentrate, in a hermetically sealed package, such as, for example. or a sachet Indicating the amount of active agent. The compounds of formula (I) are to be administered by infusion, they may be delivered, for example, from an infusion bottle containing sterile water or sterile saline solution. When the administered intravenous compounds are provided, a sterile water ampoule Injection is a &quot; : saline, in such a way that the ingredients can be mixed prior to administration.

The compounds of -. may be administered by more controlled release means by delivery devices which are well known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Pat. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,673,543; 5,639,476; 5,354,556; and 5,733,566, each of which is hereby incorporated by reference. Such dosage forms may be used to provide a slow or controlled release of one or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes , microspheres or a combination thereof, to provide the desired release profile in various proportions. Appropriate controlled release formulations known to those skilled in the art, including those described herein, may be readily selected for use with the 4-Tetrazolyl-4-phenylpiperidine groups. It encompasses simple dosage forms which are suitable for oral addition, such as, but not limited to, ampicillin, which are adapted for sustained release.

Controlled release pharmaceutical compositions may have a common goal of improving drug therapy in rebound which is achieved by their counterparts; i · :: · controlled. In one embodiment, a controlled release composition comprises a minimum amount of a 4-Tetrazolyl-4-phenylpiperidine Compound to cure or control the minimum amount of time. The V d Π L 8. g θ Π & of controlled release drugs include an extensive drug activity, a pharmacokinetics, reduced dosage and increased patient tolerance. In addition, controlled release compositions may favorably affect the onset time of the action or other characteristics, such as, the blood levels of the 4-Tetrazolyl-4-phenylpiperidine compound and may thus reduce the occurrence of side effects (e.g. , adverse events).

In one embodiment, the controlled release compositions may initially release an amount of a 4-Tetrazolyl-4-phenylpiperidine compound which readily treats or prevents either giving or diarrhea and gradually and continuously releases other amounts of the 4-Tetrazolyl-4- phenylpiperidine, to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain this constant level of the 4-Tetrazolyl-4-phenylpiperidine Compound in blood, the 4-Tetrazolyl-4-phenylpiperidine Compound can be Released from the dosage form at a rate that will replace the amount of 4-Tetrazolyl-4 The controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water or other conditions or physiological compounds. The amount of the phenylpiperidine compounds which is effective in the treatment or prevention of pain or diarrhea may depend on the nature or severity of the pain disorder and can be amenable to standard clinical techniques. Furthermore, the compositions may optionally be used to help identify the optimum effective dosage amounts. The dose required to be administered may also depend on the intended route of administration and on the degree or severity of the pain or diarrhea and should be determined according to the judgment of the patient and the circumstances of each patient in view of the clinical studies published. Appropriate effective dose amounts, however, range from about 10 micrograms to about 2,500 milligrams every 4 hours, though usually about 100 mg or less. In one embodiment, the effective dose amount will vary from about 0.01 milligrams to about 100 milligrams of a 4-Tetrazolyl-4-phenylpiperidine compound every 4 hours in another embodiment of about 0.020 milligrams of 50 milligrams, every 4 hours, and in another embodiment, from about 0.025 milligrams to about 20 milligrams, every 4 hours. The dosage amounts described herein relate to the total amounts administered; that is, if more than one 4-tetrazolyl-4-phenylpiperidine compound is administered the actual dosage amounts correspond to the total amount administered.

When a cell capable of expressing an opioid receptor is contacted by a 4-Tetrazolyl-4-phenylpiperidine compound in vitro, the effective amount will normally range from about 0.01 mg / ml to about 100 mg / L, in one embodiment , from about 50 tg in a further embodiment, from about 1 mg to about 20 tP / Lf of a solution or suspension, to a carrier or an excipient acceptable under item view.

When a cell capable of expressing an opioid receptor is contacted by a 4-Tetrazolyl-4-phenylpiperidine compound in vivo, the effective amount will range from about 0.01 mg to about 100: v / kg / of body weight per day in the range of about 0.1 mg to about 50 mg / kg of weight per day and in another embodiment about 1 mg to about 2 mg / kg of body weight of the body per day.

The 4-Tetrazolyl-4-phenylpiperidine Compounds can be evaluated in vitro or in vivo for their ability to treat or prevent pain or diarrhea prior to its use in humans. Animal model systems may be used to demonstrate the safety or efficacy of the 4-Tetrazolyl-4-phenylpiperidine Compounds.

The instant methods for treating or preventing pain or diarrhea in an animal may further comprise administering to said animal an effective amount of another therapeutic agent.

The present methods for stimulating the release of the DP1 receptor in a cell may further comprise the contact of the cell; with an effective amount of another therapeutic agent. ant i-convulsive

Examples of other therapeutic agents include, but are not limited to, an opioid agonist, an unsaturated analgesic, a non-steroidal anti-inflammatory agent, the anti-migraine agent, a Cox-II inhibitor, a snt a beta-blocker, an antidepressant, a Ca 2+ channel blocker, an anti-cancer agent, a cti-anxiety agent, an agent for the treatment or prevention of addiction disorder and mixtures thereof.

Effective amounts of other therapeutic agents are well known to those skilled in the art. However, it is well within the skill of the art to predict the range of the optimal effective amount of the other therapeutic agents. In one embodiment of the present invention, when another therapeutic agent is administered to an animal, the effective amount of the 4-Tetrazolyl-4-phenylpiperidine Compound is less than the effective amount that would be used if no other therapeutic agent were administered. In this case, without being bound by any theory, the 4-tetrazolyl-4-phenylpiperidine compound and the other therapeutic agent are believed to act in synergy to treat or prevent pain or diarrhea.

Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodin, alfaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitezene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, hydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxaphethyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethyuambutene, ethylmorphine, etonitazene-fentanyl, heroin, hydrocodone, hydromorphone, tetramethonone, ketobemidone, levorphanol, levophenylmorphan, lofentanil, meperidine, meptazinol , metazocine, methadone, methadone, metodol, mirophine, nalbuphine, narceine, noradrenorphor, norethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenenaxane, fenomorphan, phenazocine, phenoperidine, piminodine , piritramide, proheptazine, promedol, properdin, propiram, propoxyphene, sufentanil, tilidine, tramadol and their salts and the like. their pharmaceutically acceptable mixtures.

In certain embodiments, the &quot; agonist &quot; the opioid is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramidoi, oximerone, and the pharmaceutically acceptable salts and mixtures thereof.

Examples of useful non-opioid analgesics include nonsteroidal anti-inflammatory agents such as aspirin, ibuprofon, diclofenac, naprcxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, pyroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen , aminoprofen, tiaprofenic acid, fiuprofen, bucloxic acid, indomethacin, sulindac, tolmetine, zomepirac, thiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, fluphenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam and the pharmaceutically acceptable salts and mixtures thereof. Examples of other suitable non-opioid analgesics include the following non-limiting chemical classes of antipyretic analgesics, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, choline magnesium trisalicylate salicylate, salsalate, difunctional, salicylic acid] sulfasalazine and olsalazine; para-aminophenol derivatives. and pharmaceutically acceptable salts thereof including indomethacin, sulindac and etodolac; heteroaryl acids, including tolmetin, diclofenac and ketoroiac; anthranilic acids (fenamatcs), including SiO 2 db 0: 0 and meclofenamic acid; enolic acids, including oxi-cams (piroxicam, tenoxicam) and pyrazolidinediones (phenylbutazone, oxyfentartazone); and alkanones, including naburaclone. For a more detailed description of derivatives of steroidal n-steroid antagonists, see Paul A. Imcel, "Antibiotics and Antiinflammates and Agents and Drugs in Treatment of Gout, in Goodman &amp; Gilman's The Pharmacological Basis of Therapeutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R. Hanson, Antipyretic and Anti Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Voi II 1196- 1221 (AR Gennaro ed. 19th ed 1995) which are hereby incorporated by reference in their entirety. Appropriate SM-II inhibitors and appropriate 5-Lipecylase inhibitors, as well as combinations thereof, are described in U.S. Pat. 6,136,839. Cox-II inhibitors include, but are not limited to, rofecoxib and celecoxib.

Examples of useful anti-migraine agents include, but are not limited to, alpiropride, dihydroergotamine, dolasetron, ergolinol, ergocorninine, ergocryptine, ergot, ergotamine, flumedroxone acetate, fonazine, lisuride, lomerizine, methysergide oxetorone, pizotiline and the like. their mixtures. The other therapeutic agent may also be an antiseptic agent. Useful anti-hermetic agents include, but are not limited to, prochlorperidine promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, monoethanolamine of alkoxycarbonyl, azasetron, benzinamide, .climaxine, dimen-meclizine, arsenic. I, autina, bromopride, buclizine, iodine, metopimazine, oxypernidil, pipamazine, scopolamine, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron in the same manner as in Example 1,

Examples of useful adrenergic agents include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinoyl, atenolol, beunolol, becololol, bevantolol, bisoprolol, bopindolol, bttttolol. bufetolol, bufuralol, bunitrolol, butopololol, butophololol, earazolol, carteolol, carvediol, celipro.ol, cetamolol, chloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunoloi, mepindolol, metipranolol, metoprolol, moprolol, nadolol , nadoxolol, nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronetalol, propranolol, sotalol., sulfinalol, talinolol, tertatolol, tilisolol, tyrolol, toliprolol and xibenolol.

Examples of useful ariti-convulsants include, but are not limited to, acetylphenoturide, albuloin, aldoxine, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atroiactamide, beclamide, buramate, calcium bromide, carbamazepine, cinthromide, clomethiazole, clonazepam dimethadione, dimethadione, dimethadione, doxenitroin, eterobarb, etadione, ethoxymide, ethotoin, felbamate, fluorescence, gabapentin, 5-hydroxy tryptophan, lamotrigine, magnesium magnesium sulfate sulfate, mephenytoin, mebobarbital, metarbital, metetoin, 5-phenyl-hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, parametadione, phenacemide, phenetarbital, feneturide, fen- suximide, phenylmethylbarbituric acid, phenytoin, sodium feoenylate, potassium bromide, pregabalin, primidone, prozabide, sodium bromide, sputum and sodium bromide. ty ;; a..x. ts tetrantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin and zonisamide.

Examples of such antidepressants include, but are not limited to, butynedaline, caroxazone, citalopram, (S) -citalopram, dimethanine, fencamine, indalpine, indeloxazine hydrochloride, nefopam, nomifensine, oxitriptan, cxipertin, paroxetine, sertraline, thiadiazine, trazodone, benmoxine, iproclozide, iproniazide, isocarboxazid, nialamide, octamoxine, phenelzine, cotinine, roliciprin, rolipram, maprotiline, metra-iindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butylptiline, clomipramine, demexiptylline, desipramine, dibenzepine, dimethacryne, dopamine, doxepin, fluacizin, imipramine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, nortriptyline, noxyptiline, opipramol, pizotiline, propyppine, protriptyline, quinupramine, tianeptine, trimipardine, adrafinyl, benactizin, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematoporph irina, hypericin, levofacetoperan, medifoxamine, milnacipran, minaprine, moclobemide, nefazodone, oxaflozen, piberaline, prolintane, pirisuccideanol, ritanserin, roxindole, rubidium chloride, sulpiride, tandospirone, tozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan, renlafaxine , viloxazine and zirneldine,

Examples of useful channel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendilin, galopamiio, π dbefradil, prenylamine, semotiadyl, terodiline, verapamil. amlodipine, aranidipine, barnidipine, benignipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, mifilipine, nicardipinifedipine, nilvadipine, imodipine, nisoeaipma, nitrendipine, cynarizine, flunarizine, lidcflazine, na, benzyl , etafenone, fantofarone, and per-nexilin. Useful agents include, but are not limited to, acrylazole, acronazole, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperline, azacitidine, azetepa, azotomycin, batimastat, benzodepa bicalutamide, bisanthrene hydrochloride, bisnafide dimesylate, biselectin, bismethine sulfate, buprenorphine, busuifan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydroxide, carzelesine, cedefingol, clcrambucil, cyrolemycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, deeitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflorniti hydrochloride enamplatin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, erbulozole, esorubicin hydrochloride, etradernine, sodium phosphate and estramustine, ethanidazole, etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride, fazarine, fenretinide, i floxuridine, phosphate fludarabine, fluorouracil, flurocitabine, fosquidone, sodium fostríecin, gemcitabma, gemeitabine hydrochloride, hydroxyurea, ifosfamide hydrochloride, ilmofosine, interleukin I! (including recombinant interleukin II or IL2r), interferon alpha-2a, alpha-2b, interferon-alpha-1, interferon-alpha-3, interferon-alpha, gamma interferon-alpha, hydrochloride, irinotecan hydrochloride, hydrochloride acetate, thioacetic acid acetonitrate, Î ± -oleptic acetylase, β-lactam antibiotic, sodium methoxazole, β- mm u 11 ód f cy hydrochloride: x: d,? yyi.it: m'f d ina &lt; mechlorethamine hydrochloride, mmvm acetate :. and o:}, melengestrol acetate, melphalan, menogar.il, ::::::::: dd: dihydrobenzofuran, methidecarboxylate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, methotrexate, The compounds of the present invention may be prepared by the following methods: Pharmaceutical compositions according to any of the preceding claims, wherein the pharmaceutically acceptable acid addition salts of the compounds of the present invention include, for example, mycophenolic acid, dicarboxylic acid, peanutine, pegaspargan, peliomycin, pentamusine, peplomycin sulphate, perfluorine, pipobromane, piposulfan, pyroxantrone hydrochloride, plicamycin, plomestane, sodium porphyromide, porphromycin, prednimustine, procarbazine hydrochloride, puromycin , puromycin hydrochloride, pyrazofine, riboprine, roglethimide, safingol, safingol hydrochloride, veterinary drug, simtrazene, sodium sparphosate, spparomyomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrini, streptozoline, sulofenur, talisomycin, tecogalan sodium, tegafur, teloxantrone chloriarate, temoporfin, teniposide, teroxirone, testolactone, thiamiprin, thioguanine, thiotepa, thiazoturin, triazasine phosphate, trimethoxate trimethoxate, trimetrexate glucuronate, triptorelin, tubulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfine, diblock islldd sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinglicinate sulphate sulphate, dl sulphate sulphate. tartrate of the double diphenylmethyldisulfonate, and the like. C y-C y-C y-Cpl-Cpl-Cpl-Cpl-Cpl-Cpl-Cpl-Cpl-

Examples of other phenolic compounds, 20-epi-1,4-diiodide. tm. abiraterone; c anti-cancer include, but not v &gt;: &quot; ·! - · · :; V, V. V., 3, 4, 5; acilfulvene adeetpe-noi; a-doz-el-esin-; ootox: Oi: ¾¾¾ of ABL-TK; Oxax; xo; ai & b &amp;amp;xystx;amifostine; Sodium acid: ¾¾ 1: 1: 1: 1: : xo :; anagr; anastrozole; andrografolide; loXbb.tkxroo of angiogenesis; antagonists D; s: ixososi .; srss d; antareiix; prctef.no 1 sfcrfd'geeéridâ anti-dorsalization; oeroxixxoxs anti-androgen pro-prophylaxis; aniline and methyl ester; anti-neopiaston; oligosaccharides: 1 's - Bivalves; bifloxacin; moculators of the apoptosis gene; regel &amp;amp; a-ap: apoptosis; apurinic acid; ara-CDP-DL-PTBA; deaminase of Hxg: x: n,; .. n.x; asulacrine; atamestane; atrimustine; axinastatin L; axinastatin 2; axinastatin 3; : aes.setred; azacoxxna; azasyrosin; baccatin III derivatives; balanoi; batimastat; BCR / ABL antagonists; benzochlorins; ioenzoylstaurosporine; beta lactam derivatives; beta allele; beta-chlamycin B; betulinic acid; FGFb inhibitor; bicalutamide; bisantrene; bisaziridinylsilmine; bisnafide; bistratien A; bizelesine; breflato; bropirimine; budotitan; butionin sulfoximine; calcipotriol; calfostin C; campto-tecine derivatives; canaripox IL-2; capecitabma; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; GAPN 700; cartilage-derived inhibitor; carzelesin; inhibitors of casein kinase (ICOSIi castanospermine, cecropma E, cetrorelix, chlorins, chloroquinoxalin sulfonamide, cicaprost, cis porphyrin, cladribine, analogues of elomifene, clotrimazole, colismicin A, colismicin B, combretastatine A4, and combretastatine , conoxynin, expoxynucleotides, cyclosothromycin, cyclosothromycin derivatives, cyclosothromycin derivatives,

cycloplatam; oxse: x.u :: xpx; Oi φ c: χ; χρ; ο a; X is O, X is O; X. i οχ:,; X Xx: X. XX; The Od 0 '.1 i-x: i MfeJ decitabine; dehydrodi demnin B; fesboxoi: id; dexamethasone; dexifosfamxda; aexrazoxane; dexverapa m i 1; * 1 x a ti d b &amp; nenethenyl B; diethylnorespermine; dx-ítxíirt ··· 1 ·· x xo x: x o.:. d x o o; dihydrotaxol; 9-dioxamycin; xx - &amp; $ p i r omustlna-; sweet taxei-; sweet rolls; dolasetro-n ·; doxycycline; droloxifene; dronabinol; ctuocarmicma SA; ebselen; S! e. A d e. and d r e c ο I oma b; -¾ fl tu: si i is ,; ee emanation; emitefur; epirubicin; epristeride; estrogen analogues; a &amp;amp;ists;estrogen;ethanidazole; etoposide phosphate; exemestanc; fadrozole; fazabab; fenretinide; f i] grastím; f inasteride; FIG. flezelastine; fludarabine; fluorodaunorunicin hydrochloride; forfen i ... mex; formestane; I; ϋ &amp;Z; z i m s is i; fotemustine; gadolinium texaphyrin; gallium nitrate; gallocitabine; ganirelix; gelatinase inhibitors; gemcitabine; giutatine inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; similar growth factor receptor 1 inhibitor I insulin; interferon agonists; interferons; interleukins; lobenguano; iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole; iso-homo-halichondrin B; itasetron; jaspiacinolide; ca-halide F; Lamellar N-triacetate; lanreotide; leinamycin; lenograstim; lentinium sulfate; leptolestatin; letrozole; leukemia inhibition factor; leukocyte alpha interferon; leuprolide + estrogen t progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; platinum-lipophilic compounds; lysoclinamid 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lutetocan; lithium texaphyrin; 1-yl peptides; maytansine; manostatin A; mx masoprocol; maspma; inhibitors of intromission; aa matrix on metalloproteinase; menogani; meroarena; methioninase; metoclopramide; of MIF; miiitptittt-pò .; miltefosine; ml; MioMm;

RNA to the structure in the paired; niltoguaz-oria; ioidadabfc &amp; l · ·· ;; analogues of FFi ± aiiaea * a; m; .toni; .do; saporma to the growth factor of mitotoxin fibroblasts; its toxantrone; . Fig. : f; 1, 2, 3, 4, 5, 6, 7, 8, . &lt;. ··. ·. -:W ; i c bt Li Ο Ί-: ·> - 1. * fi .t. The polypeptide of the polypeptide of the polypeptide of the polypeptide of the polypeptide of the polypeptide of the polypeptide of claim 1, The pharmaceutically acceptable salts of the pharmaceutically acceptable salts and pharmaceutically acceptable carriers are pharmaceutically acceptable carriers. piipi agents; mustard seeds; rn. B cupu rr; extract aa wall of the mycobacterial cell; N-acetylalanine; covalent benzyl amides in the N-position; nafarelin; nagrestip; naloxone * pentazocine; napavma; nafterpina; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; antioxidant of nitroxide; nitrulline; 06-benziiguanine; octreotide; ocicenone; oligonucleotides; onapristone; ondansetron; oracma; cytokine oral inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoyl-hyoxin; pamidronic acid; panaxitriol; panomifene; parabactin; pazeliptina; pegaspargase; peldesin; pentosan sodium polysulfate; pentostatin; pentrozole; perflubron; perfosphamide; perilyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; activator inhibitor? platinum complex; compounds of the platinum-triamine complex piotinoi; porphimer of oily; porfiromycin; prednisone; propyl-bis-acridone; prostaglandin loipiocysteroids of proteasome; modulator immizèziv based on protein A; pyrazole of the Pseudomembrane. ptotolnase cmase C; oxyethylsilyl; protein or phosphatase; protein; purine phosphorylase; potentiated; pyrazoloacridine; pyridoxylated polyoxyethylene and polyoxyethylene; i-ai antagonists; raitítrexed; raraosetron; ras protein transferase inhibitors; irú.bí <kiTm de ras; Ras-GAP inhibitor; 1a-dl-dystroglutamine of the α-amino acid; The;; retinamide BII; ; ιΙα-Ια - 'cíde;

roquinimex; rubiginone 31; rubecoxyl; safíngol; saintcpina; SarCNU; sarcofitol k (sargramostim; simetic mimetics; semustine; Malignant; senescence derivative; parallel oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; Sodium borate, sodium phenylacetate, solverol, somatomedine binding protein, spironolactone, spasmocin D, aspirin, splenopentine, spongistatin 1, squalamine, differentiated cell inhibitors, differentiated cell division inhibitors, stromelysin inhibitors , sulphosine, superactive vasoactive intestinal peptide antagonist, suramin, swainsonine, synthetic glycosaminoglycans, thalimustine, tamoxifen methiodete, tauromustine, tazarotene, sodium tecogaine, tegafur, telurapiril, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaxide, tetrazornine thalocastin; thrombopoietin mimetic; thimaifasin; agonist of the thymopoietin receptor; thymotrene; thyroid stimulating hormone; tin ethyi-ethiopurine; tirapazamine; titanocene bichloride; topsentin; toremifene; all-powerful factor of differentiated c; thymidine inhibitorsTretinoin; triacetyluridine; triciferin; trimetrexate; triptorelin; tropisetron; torrential; inhibitors of tyrosine ΐΐΐΐοόόρίοο "; inhibitors òs; uBC ;:; inhibitory factor of urogenital sinus growth; vapreotide receptor antagonists; vir ioi ιλο B; erythrocyte gene therapy in the erythrocyte system: lymphocytes; ..................... :Hi. and, in the case of a single object,

Therapeutic agents useful for the treatment or prevention of a dependence disorder include, but are not limited to, methadone, cesipramine, amantadine, fluoxetine, buprenorphine and opiate, 1-phenoxypyridine or a serotonin antagonist.

Examples of useful antianxiety agents include, but are not limited to, benzodiazepines, such as, alprazolam, chlordiazepoxide, cionazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; agents which do not contain benzodiazepine, such as, buspirone; and tranquilizers, such as barbiturates.

Examples of useful anti-diarrheal agents include, but are not limited to, loperamide, diphenoxylate with atropine, clonidine, ethoxide and cholestyramine. The 4-Tetrazolyl-4-phenylpiperidine Compound and the other therapeutic agent may act in an additive form or, in an environment, synergistically. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compound is normally administered and is the other therapeutic agent; for example, a composition comprising an effective amount of a 4-Tetrazolyl-4-phenylpiperidine Compound, an effective amount of another therapeutic agent, may also be administered. Alternatively, a composition containing an effective amount of a compound of and a different composition, comprising an effective amount of another agent may be administered concurrently. In another embodiment, an effective amount of the pre-subsequent amount of an effective amount of another therapeutic ingredient is admixed. In this embodiment, the compound of the invention is administered while another agent exerts its therapeutic effect or the other therapeutic agent is o1io . air. .o.-d · ,; while -000 is composed of &lt; 1 &quot; o001: 1 -i -io: t0 i0rpo ;; It exerts its preventive or therapeutic effect for the treatment or prevention of pain or diarrhea. The composition of the present invention is prepared by a process which comprises mixing a 4-Tetrazolyl-4-phenylpiperidine Compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient . The mixture is made using known methods to mix a compound (or salt) and a pharmaceutically acceptable carrier or excipient. In one embodiment, the composition is prepared such that the 4-Tetrazolyl-4-phenylpiperidine Compound is present in the composition in an effective amount. The present invention encompasses kits which can simplify administration of a 4-Tetrazolyl-4-phenylpiperidine to an animal. A typical kit of the present invention comprises a unit dosage form of a 4- ΤΪ ΤΪ ΤΪ ΤΪ P P P P P P P P P P P P Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π Π The sterile dosage form is a sterile package containing a gestatethideide of a tetrazole compound of formula (I) or a pharmaceutically acceptable excipient. The kit may further include a label or apparatus which comprises the use of the 4-Tetrazolyl-4-phenylpiperidine compound to treat either pain or diarrhea. The kit may comprise a dosage form In another embodiment, the kit comprises an effective amount of the 4-Tetrazolyl-4 compound of the other agent, for example, a vial containing an additional amount of the other 4-Tetrazolyl-4 Examples of other therapeutic agents include, but are not limited to, the pharmaceutically acceptable acid addition salts and the like. before.

The kits of the present invention may further comprise a device which is useful for the administration of the unit dosage forms. Examples of such devices include, but are not limited to, syringes, bags, adhesives, ointment bags and inhalers.

The following examples are constructed to aid in understanding the present invention and should obviously not be construed to specifically limit the invention described herein and the claims. Such variations of the present invention, including the substitution of all equivalents now known or later developed which would be within the scope of those skilled in the art and changes in formulation or minor changes in the experimental design, are to be considered falling within the scope of the present invention and incorporated herein.

1-7 relate to the methods of the present invention. 5.1 Example 1: Synthesis of Compound A &amp;

Scheme 11 / //

. If. &gt; C &lt; / RTI &gt; 1, IOM .txt / **% v \ / Vv / £ Wxxvx ^ \ / -n / \ Λ. WAVA V Λ \ w # V / \ »Λ &quot; To a solution of the compound (A1c 3.0 mmole) of compound (B) (3.0 mmole) in 10 ml of 1,2 equivalents of DIEA. The mixture was stirred at 80 øC for overnight. The reaction mixture was cooled, diluted with ethyl acetate and washed with water (20 mL x 2). The aqueous layer was extracted once with ethyl acetate (25 mL). The combined organic phases were dried (MgSO e) and the solvent was removed on a rotary evaporator. The residue was purified by column chromatography; 5% EtOAc / 70% EtOAc / 70% hexane) to give the desired product of compound (C) as a colorless solid. Compound (C): Yield: 85%, purity (HPLC) &gt;97%; MS: m / z 381.3;  € ƒâ € ƒâ € ƒNMR: 6 2 mi: ··· ;,; 9 (m, 4H), 2.25-2.35 (m, 2H), 2.4-3.2 (m, 4H), 2.91-3.03 (m, 2H), 4.0 (t, 1H), 7.1-7.4 (m, 2H), 7.3-7.0 (m, 2H)

Scheme 12

/ "&Quot; T

W

VtVnwiMv.VMMVMwWWinT / &quot; and. (4) (4) and (4) and (4) and (4) and (4). Vy w Λ ™. &Lt; ' u I ò! / y. To a solution of the compound (â, €) (0.degree.) In toluene (1 ml) was added 2 equivalents of and 0.1 equivalents of b: U: The reaction mixture was stirred at reflux temperature for 24 hours. The precipitate was evaporated in vacuo to give the title compound as a white solid. The solvent was evaporated in vacuo to give the title compound as a white powder. The organic extracts were evaporated and the solvent was evaporated. The extracts were dried over magnesium sulfate and evaporated to dryness. was treated with 5 g of silica gel. The product was collected by elution with 5% Et3 N, 25% ethyl acetate and hexane and 704, then 10% cCi, EtOAc at 40 The title compound was prepared as a white solid (50% yield) as a white solid (50% yield) as a white solid. %, purity (HPLC)> 97%; MS: m / z 424.2; 1 H NMR (MeOD): δ 2.3-2.5 (m, 4H), 2.66 (m, 6H), 3.4-3.5 (m, 2H), 3.9 (t, 1H), 7.1-7.3 (m, 15H).

5.2 Example 2: Synthesis of Compound ACY

Scheme 13

To a solution of compound (D) (3.0 mmole) and compound (B) (3.0 in 10 mL of DMF was added 1.2 equivalents of DIEA. The mixture was stirred at &quot; The residue was diluted with ethyl acetate and washed with water (20 ml). The aqueous layer was extracted with dichloromethane and dried (MgSOâ, ") The phases were washed with dichloromethane (25%) and combined if the solvent was evaporated on a rotary evaporator. The residue was purified by flash chromatography (25%) as a white solid (25%). to 70%) to give the desired compound (E) as a colorless oil, to give the title compound as a colorless oil: 80% purity (HPLC): 97% z 406.2; m% of

To a solution of compound (E) (4.0 mmol) in 15 mL of p-xylene was added 1.1 equivalents of Me3SnN3. The mixture was stirred at reflux temperature under argon for 36 hours. The mixture was cooled and poured into 150 mL of 1 M NaOH. Diethyl Itur (150 mL) was added and this solution was allowed to stir at room temperature for 1 hour. The layers were separated and the aqueous layer was extracted with diethyl ether (150 mL x 1). The aqueous layer was acidified to pH 6.3 with acetic acid / ammonium acetate. The filtrate was washed with water (100 mL) and triturated in cold methanol to give the product as a white solid. Chromatography on silica gel with ethyl acetate and chromatography on ethyl acetate: methanol afforded compound (ACY) as a white solid. C (compound ACY) (5.0 g, 11.14 mol) in methanol in 200 ml of dichloromethane (200 ml) was added. (1.08 g, 1.11 mmole) in hot water (5 mL) was added to give

: i: Clear. The solution was allowed to cool slowly at r.t. times and then filtered to give the sulfuric acid salt of the 5Î ± (ACY): (1.21 g, 73%) as a colorless oil. of needle needles. (ACS) salt (sodium salt): purity: 97% m 12: MS: m / z 499.22; &quot; H & 2 1 δ 2.2 2-2 1 22 2 1), 2; 22 et, 2::?: 2.23 (c, 2H), 2.7-2.85 (m, 2H); 4-yl), 2.2-2.12-3.3-3.4 (broad s, 2H), 7.22-7.2 (m, 22); 7.3-7.4 (m, 4H ), 7.1-7.7 (8H, m).

5.3 Example 3: Synthesis of Compounds ADI and BDI

Scheme 15 'f ../ W | sd

ACS.

In addition, R f

A solution of the compound (ACY) (0.45 mmole) in methylene chloride (50 ml) was added dropwise to a solution of the compound (ACY) DMF, triethylamine (0.54 mmol) was added, followed by an alkylating agent (Pr 2) (CH 2 CH 3) (0.54 mmole) The resulting mixture was stirred at 80 ° C After the reaction was complete, the cooled mixture was partitioned between tetrahydrofuran and brine, and the organic phase was separated, dried (MgSOâ, ") and the solvent was removed on a rotary evaporator to give (DMF) was obtained as a white solid from the mother liquor: yield: The title compound was prepared as a white solid, 24%, purity (HPLC)> 97%, mm / z 549.3 (M + 1);  € ƒâ € ƒâ € ƒNMR: δ1. 6H), 9 (m, 4H), 3.05 (s, 8.8 (t, 3H), 3.2-3.4 (m, 4H), 3.95 (q, t, 2H), 7.15 (m, 1H). The mother liquor contains the compound MSI and the compound (BDSs which were separated using standard separation procedures.

5.4 Example 4: Synthesis of Compounds ADQ and BDQ

Scheme 16

pq / c - \ JÁ-% Kr \ M &gt; / &quot; &quot; To a solution of the compound (ACY) (0.45 mmol) in anhydrous DMF was added triethylamine (0.511 mmole) ), followed by an alkylating agent (Br (CH 2) (0.54 mmole).

The resulting mixture was stirred at 80 ° C overnight.

After the reaction was complete, the cooled mixture was partitioned between ether and brine and the organic phase was separated, dried (Na2 SO4) and the solvent removed on a rotary evaporator to give a colorless gum to pale yellow. trituration in ether / hexanes or ether / ethyl acetate (1: 1, 10 mL) precipitated the compound (ADQ) as a white solid from the mother liquor: yield: 59% purity (HPLC )> 97%, MS: m / z 570.2 (M + 1); 1 H NMR: δ: 2.1-2.3 (m, 6H), 2.6-2.7 ( m), 2.75 (s, 3H), 2.85 (d, 4H), 3.25-3.35 (m, 1H), 3.6 (t, 2H), 4.65 (t, 2H), 7.15-7.2 (m, 1H), 7.92 (m, 6H), 7.38-7.45 (m, 8H) The mother compound contains the compound (BDQ), which were separated from each other by conventional separation.

5.5 Example 5: Synthesis of ACZ and BCZ Compounds

Scheme 17,. (I.e., (ii)). Ϊ ': Xvwí &quot; Λ: V ····· &quot; A solution of the compound (ACY)) 0.4 mol, in anhydrous DMF was added (0, 1%) as a white solid. 54 mmol), followed by 2-bromoacetamide = λ Tm mmole). The resulting mixture was heated at 80 ° C overnight. After the reaction was complete, the cooled mixture was partitioned between ethyl acetate and brine, and the organic phase was separated, dried (MgSO 4) and the solvent was removed on a rotary evaporator to give a light yellow gum. Flash chromatography (SiO 2, ether: methanol: ammonium hydroxide (1000: 4: 1)) provided the title compound (ACZ) as a white solid. (Yield 48%). Compound (ACZ): purity &gt; 97% (HPLC); MS: m / z 506.2 (M + 1); 1 H-NMR (DMSOd 6): δ 1.8 (m, 2H), 2.2 (m, 4H), 2.6-2.8 (m, 6H), 5.35 (s, 2H), 7:? = 7.75 (m, 16H), 7.7 (m, 1H).

Further chromatography provided the compound (BCZ).

5.6 Example 6: Synthesis of Compound AFD

Example 18 o ^ n | ννΊ j, fiw. .......... . SOCIs Ο HCr &quot; \ | / \ li \% ê \ twnuj m

A suspension of chloroform (15 g, 72 mmol) in chloroform (150 ml) was added dropwise to the solution of the title compound. 20 ml of thionyl chloride (270 mmol). After addition of the thionyl chloride, there was added ethyl. ml of dimethylformamide and the resulting solution was heated at reflux temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure to provide 4-bromo-2,2-diphenylbutyric acid chlorite (compound (G)) as a light yellow oil, which was used in the next step without more purification. To 100 mL of a saturated aqueous solution of ilogol, 50 mL of a 2 M dimethylamine solution in tetrahydrofuran was added. The resulting solution was cooled to 0 ° C and a solution of the compound (6), prepared as described above, was dissolved in 110 ml of toluene and added dropwise. The resulting solution was stirred for 1/2 hours. The aqueous and aqueous layers were separated from the reaction mixture and the aqueous layer was extracted with 30 ml of toluene and then extracted 3 times with 100 ml of chloroform and brine ··· s-í · · organic phases. The organic extracts were washed with water (133 ml), dried (Na2 SO4), dried (Na2 SO4) and evaporated to dryness. In the bosom of the so-called 'sobotil', to be οοίο

Scheme 19

(1) To a surplus of the compound (H) 3 (0 mole) and the compound of formula (I) compound (B) (3.0 mmole) in 10 mL of DMF was added 3 equivalents of Na 2 CO &gt; 3. The mixture was stirred at 80 &quot; C for 3 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with water (20 mL x 2). The aqueous layer was extracted once with ethyl acetate (25 mL). The combined organic layers were dried (Na2 SO4) and the solvent was removed on a rotary evaporator. The residue was purified by column chromatography (5% NEt / 25% EtOAc / hexane at 70-171) to provide the product of compound (I) as colorless crystals: (yield: 81% ), purity (HPLC):> 97%, MS: m / z 452.2; NMR (CDCl3): δ, ν-δ, δ (m, 4H), 2.2 (m, 2H), ( m), 2.2-2.2 (m, 2H), 2.9 (m, 2H), 3.0 (3H, 3H), 7.2-7.3 (m, 3H), 7132-7.5 (m, 12 H).

Scheme 20

Uwwswwv.

Urea reflux, dibutyl tin oxide

To a solution of compound Olp (-O-, 5 mmol) in K 2 of toluene provided 2 equivalents of MeSYS and 0.1

solvent under reduced pressure. The crude materials were dissolved in CH₂Cl₂ and charged to a stream which was charged with 5 g of silica gel. 4-Chromatography under pressure was performed by elution with 5% Et 3 N, 25 I ethyl acetate and 70% hexane, then 10% Et 3 N, 1 to 40%, 50% hexane and finally eluted with 2% NH 3 / H 2 O, 15% methanol and 83% EtOAc. This afforded the compound (AFD) as a solid (yield: 35%); purity &gt; 97% (HPLC); MS: m / z 4 95.2; NMR (DMSO d 6): δ 2.2 (broad s, 3H), 2.3-2.4 (m, 2H), 2.5 (m, 3H), 2.6-2.7 (m, 2H) 2H), 2.9 (broad s, 3H), 3.3-3.4 (broad s, 3H), 7.2-7.3 (m, 3H) , (m, 4H), 7.4-7.5 (m, 8H).

5.7 Example 7: Synthesis of Compounds AFE and BFE

Scheme 21 # -s: i). S f. &quot; HX &quot;. . w &gt; ^ 7 - &quot; * 'K AFD' &quot; ay &gt; \. Nv

BFE To a solution of the compound (AFD) (0.40 mmol) in dry DMF was added triethylamine (0.45 mmol), followed by the compound of Compound A (KOH). 0.45 mmol) The resulting mixture was stirred at 80 ° C overnight and then the cooled mixture was poured into ice.

NaOH (50 ml) and extracted with ethyl acetate (2

SE x 107 mL). The organic extracts were dried and the solvent evaporated to give a gum. Flash chromatography of the ammonium residue (10: 1: 33) afforded the title compound as a colorless gum: (yield 69%); (S, 3H), 1.33 (m, 3H), 1.33 (m, 1H) 33-33 Î'(m, 1133, 3.3-3.4 (m, 4H), 5.35 (s, 2H), 1.33-7.3 (m, 13β, 7.8 [br s, 1H).

Subsequent chromatography afforded the compound (BFE). 5.8 Example 8: Synthesis of AFV and BFV Compounds

Scheme 22

r = 1; v Λ X ..... u · · · · · f f f Ó Ó Ó Ó Ó Ó Ó Ó Ó Ó Ó Ó Ó Ó? s.-IIM

: To a solution of the compound (AFD) (0.40 mmol) in anhydrous DMF was added triethylamine (0.45 mmol) followed by an alkylating agent Br 33 (33: 31353: nC73 (0.45 mole).

The resulting mixture was stirred at 83 ° C overnight. After the reaction was complete, the cooled mixture was poured into 1M NaOH (150 mL) and extracted with ethyl acetate (2 x 160 roll). The organic extracts were dried (MgSO4) and evaporated on a rotary evaporator to give a gum. Chromatography of the residue: ether: methanol: ammonium hydroxide. afforded compound (AFV) as a colorless gum: (yield: 261), purity> 971 (HPLC), MS: m / z 631.33 + i); (S, 3H), 2.3-2.4 (m, 5H), 2.75 (s, 3H), 3.33 (br. , 3.43 (m, 6H), 3.5 (m, 3H), 4.65 (m, 1133, N-1-F, S (ro, 16H).

Further chromatography gave the compound (BFV). 5.9 Example 22: Receptor Binding Affinity Assays The following example will demonstrate that 4-Tetrazolyl-4-phenylpiperidine Compounds bind to the μ- or SRO-I receptors and, therewith, are useful for the treatment or prevention of pain or diarrhea. 5.9.1_Materials and Processes

Preparation of Receptor Membrane

All reagents were obtained from Sigma (St. Louis, Mo.), unless otherwise indicated. The membranes of recombinant HEK-293 cells expressing a human opioid receptor-like receptor (Perkin

Elmer, Boston, MA) are prepared by lysing the cells in ice-cold hypotonic buffer, 2.5 mM iMqClI, 50 mM HEPES, pH 7.4) (10 mL / 10 cm dish), followed by homogenization with fabric mill / teflon pinion. The membranes are collected by centrifugation at 30,000 x g for 15 minutes at 4 ° C and the pellet resuspended in hypotonic buffer to a final concentration of 1-3 mg / mL. Protein concentrations are determined using the BioRad protein assay reagent (Hercules, CAI with bovine serum albumin as standard. Aliquots of the SRO-I receptor membranes are stored at -80 R.v

Miy, respectively, with 5-20 mg of membrane protein / microtube, in a final volume of 500 ml of ligation: dgCl; 2.5 mM EDTA, 1 mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). Reactions were made in the presence of increasing concentrations of unlabeled nociceptin (American Peptide Company, Sunnyvale, CA) or naloxone, pSC '. SRC-1 and æm, respectively. All reactions were performed on polypropylene plates with 96 microtubes bottomed for 1-2 hours at room temperature. Binding reactions terminated by rapid filtration on 96-microfilter Unifilter GF / C filter plates (Packard, Meriden, CT), pre-soaked in 0.5% polyethylenimine, using a 96-well tube pickup device ( Brandel, Gaithersburg, MD) followed by the performance of three filtration washes with 500 μl of gaseous-cooled binding buffer. The filter plates were then dried at 50 ° C for 2-3 hours. A BetaScint scintillation cocktail (Wallac, Turku, Finland) (50 æl / microchrome) was added and counts were counted using a Packard Top-Count for min / microtubes. The data is arialised using the functions of the adjustment of the comparison curve at a given site, in GraphPad PRISM v. 3.0 (San Diego, CA). 5.9.2_ Receiver Connection Data μ

Generally, the lower the Ki value, the more effective the compounds of 4 ···;. q 1 s r r:.;.).). 1-yl) -piperazine hydrochloride. in or prevention of pain or diarrhea. 4-Tetrazolyl-4-phenylpiperidine compounds will have a Ki (nM) If about 300 or less, for binding to μ opioid receptors. In other embodiments, the compounds of 100 or less. In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of the present invention will have a Ki (nM) of about 10 or monos. In yet another embodiment, the compounds will have a Ki (st) of about 1 or less. In another embodiment, the compounds will have a Ki (nM) of about 0.1 or less. Compound AFD, an exemplary 4-tetrazolyl-4-phenylpiperidine, has a Ki (nM) of 3.2 for binding to μ opioid receptors. 5.9.3_Retrous Data of the ORS-1 Receptor

Generally, the lower the Ki value, the more effective the 4-tetrazolyl-4-phenylpiperidine compounds are in the treatment or prevention of pain or diarrhea. Typically, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have a Ki (nM) of about 10,000 or less, for ORR-1 receptors. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have a Ki (nM) of about 2000 or less. In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have a Ki (nM) of about 1,000 or less. In yet another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have a Ki; of about 100 or less. In yet another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have a Ki (nM) of about 10 or less. 5.10 Example 23: Functional YS Activity of the μ Opioid Receptor and SRO-1 The following example will demonstrate that the 4-Tetrazolyl-4-Phenylpiperidine Compounds stimulate Ku-1 receptor function. and, of course, (are useful for the treatment or treatment of the subject or thyroid disease, 5.10.1

Materials and Processes, as appropriate. The assay reactions are prepared by sequentially adding the following reagents to the binding buffer (10 mM NaCl, 10 mM NaCl, 20 mM HEPES, pH 7.4) on ice (final concentrations indicated) : membrane protein (0.066 mg./mL for the ORS-1 receptor and 0.026 mg / ml for the μ- receptor), saponin (10 mg / ml), GDP (3 mM) and (IgG nM; NEN) . The prepared membrane solution (190æL / well) was transferred to 96-well polypropylene plates containing 10 æl of stock 20x stock solution of the agonist nociceptin, prepared as dimethylsulfoxide (&quot; DMSO &quot;). The plates were incubated for 30 minutes at room temperature with stirring. The reactions terminated by rapid filtration on 96-well Unifilter GF / B filtration plates (Packard, Neriden, CT) using a 96-well 96-well tissue collector (Brandel, Gaithersburg, HD) followed by three filtration washes with 200 10 mM Trithidic Ice-Cooled Binding Buffer, 10 mM, pH 7.4). The filter plates were then dried at 50 ° C for 2-3 hours. A BetaScint scintillation cocktail (Wallac, Turku, Finland) (50 μl / well) was counted and the plates counted using a Packard Top-Count for 1 min / wells. The data analyzed using the sigmoid dose-response curve fitting functions in GraphPad PRI3M v. 3.0 (San Diego, CA). . concentration of a compound of the μ receptor response. The 4-Tetrazolyl-4-phenylpiperidine Compounds usually have a Î »5 C of about 5,000 or less, stimulate the Î ± -opioid receptor function. In an EC50 μM GTP (nM) In yet another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have a CE5C of λmax (nM) of about .ISO or less. In yet another embodiment, 4-Tetrazolyl-4 In yet another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have a 1 Ό Ό Ό? (nM) of about 0.1 The percentage of Emax of μ-GTP is the maximum effect caused by a compound relative to the effect caused by [D-Ala2, N-methyl-Phen4, Gly-O15] -encephalin (&quot; DAMGO &quot;), an agonist the γ-GTP Emax value (%) measures the efficacy of a compound for treating or preventing pain or diarrhea. Typically, the 4-Tetrazolyl-4 -phenylpiperidine will have an Emax (%) of μ-GTP greater than 50%. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have an Emax Ti ·; In yet another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have a γ-GTP Emax GM of greater than 88%. In yet another embodiment, the 4-Tetrazolyl-4 -phenylpiperidine will have a Emax (%) of μ-GTP greater than 100%. :S. The SRO-1-GTP EC is the concentration of amide which provides 50% of the maximum response to the compound in the peridine normally having a 5RO-1 cervix 10,000 or less, stimulate that of the opioid SRO receptor. In one embodiment, the &quot; 4-Tetrazolyl-4- Cp U.COC 0 NU O: i: f. (S) : '&quot;;;; U Y 'O; 0 0 ::::: V; Y: Y: 1,000 or less, M is as the compounds of &lt; : - tutrdí: oll: t · j. n: rltdíuttd: tt; o? and Γ uma uma uma uma uma uma uma uma uma uma uma uma uma uma -. (nM) of about 1.00 or less. In yet another embodiment, the compounds will have a 0: 1 SRC-1MMT solution. 50 or less. In yet another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have an SRO-1-GTP (EC 50) of about 10 or less. The percentage of Emax a and SRO-1-GTP is the maximum elicited by a compound relative to the effect caused by nociceptin, an ORS-1 agonist standard. Generally, the Emax value (%) of ORS-1-GTP measures the efficacy of a compound for treating or preventing pain or diarrhea.

Typically, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have a greater than 50% SRO-1-GTP Emax (%). In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have an ORX-1-GTP Ernax Md of greater than 75%. In yet another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have an EROX (%) of ORS-1-GTP greater than 88%. In yet another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will have an Emax of ORS-1-GTP of greater than 100%.

Claims (9)

JNv H 'N% \\ · g'; t '/ -M, &lt; tb &gt; THE? A pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof, wherein: At ?, is C3-C8 cycloalkyl, phenyl , naphthyl, anthryl, phenanthryl or heteroaryl (having 5 to 7 ring atoms), each of which is unsubstituted or substituted with one or more groups represented by R2; â € ƒâ € ƒâ € ƒto be phenyl, naphthyl, anthryl, phenanthryl, or heteroaryl (having 5 to 7 ring atoms), each of which is unsubstituted or substituted with one or more groups represented by the symbol; G represents H atoms, general formula -L- · · € · ύΐ; , - (alkylene or (alkylene or R 1 is H, C 1 -C 8) alkyl, or a group of the general formula (I): ## STR4 ## R 2 and f 'are each independently halogen, -alkyl-O (C 1 -C 6 alkyl), -NH (C 1 -C 3 alkyl) or -N s; (C 1 -C 4 alkyl), -CH 2 N (C 1 -C 4 alkyl), or (C 1 -C 6) alkyl, wherein R 4 is H, -NH2, -C (O) NH2, -C (O) NHOH, -C (O) NH (alkyl &gt; d: gwC'i ', C (O) N (C1 -C4 alkyl) 2, -SO2 NH (C1-4 alkyl) -SO2N (C1 -C4 alkyl): H atoms, -OH, -CN, (C1 -C4) alkyl, phenyl, naphthyl, anthryl, phenanthryl or heteroaryl (having 5 to 7 ring atoms) , each of which is unsubstituted or substituted with one or more groups represented by R 4 and m is the integer of R 4 and n is whole number from 1 to 4; Ww. &Lt; / RTI &gt; 0 o ^ Λν ·. »Λ · Λν &quot; (,),,,, FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU,,,,,,,,,,,,,,,,,,,,,,,,,,,,. !? ·; · &Gt; or a pharmaceutically acceptable salt thereof, wherein: Ar3 is phenyl, naphthyl, anthryl, phenanthryl, or heteroaryl (with 5 to 7 ring atoms), each of which is substituted or unsubstituted or substituted with one or more groups represented by the symbol R 2, G 2 is H, -L- (O-CH 2), -OCH 3, - [ (C 1 -C 6) alkyl, or - (C 1 -C 6) alkylene, -C (O) NH (C1 -C4 alkyl) -C1-4 alkyl; or -C (N) -C1-6 alkyl R2 and c are each independently halogen, -alkyl-C1-6-alkyl, -NH-C1-6-alkyl, or -N (C1- C3) alkyl, R4 is H, C1-4 alkyl, C1-4 alkyl, C (C4-C4 alkyl), or C1-4 alkyl; -NH 2, -C (O) NH 2, -C (O) NH 0 H, -C (O) NH (C 1 -C 4 alkyl), C (O) N (alkyl, -OH, -OH, -CN, -cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl or heteroaryl groups (5 to 7 atoms in the group); each of which is unsubstituted or substituted by one or more groups R4, m is an integer from 0 to 4, and n is an integer of 1 to 4,  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒR1 is a compound of the formula: Compound or a salt of the compound, acceptable under Accordingly, according to the present invention there is provided a compound of formula (I): wherein R 1, R 2, R 3, and Ar 2 are phenyl groups. A compound or a pharmaceutically acceptable salt of the compound of claim 2, wherein the symbol is a phenyl group. A compound or a pharmaceutically acceptable salt of the compound according to claim 1 or 2, wherein m = 1 and G = H atom. Compound or a salt of the compound, according to claim 1 or 2, characterized in that R6 is -C (O) NH2, -C10) NH (C1 -C12 alkyl) -C (O) N (C1 -C4 alkyl) (C1 -C4 alkyl) or -C1-3 alkoxy. The compound or a pharmaceutically acceptable salt of the compound according to claims 1 or 2, wherein p = 0 and the symbol q = 0. A salt of the compound, acceptable under the provisio nity of compounds 1 or 2, wherein the compound G represents a group of phospholipid (O) NH2, (CH2) p -CH (O): bb is 1, A compound or a pharmaceutically acceptable salt of the compound according to claims 1 or 2, wherein p = 1.10 is characterized in that it comprises an effective amount of a compound or a pharmaceutically acceptable salt of the compound of claim 1 or 2 and a pharmaceutically acceptable carrier or excipient. Composition according to Claim 10, characterized in that it further comprises an opioid analgesic, a non-opioid analgesic or an anti-emetic agent. Composition according to Claim 10, characterized in that it further comprises an anti-diarrhea agent. Kit, characterized in that it comprises the composition according to claim 10. A compound having the formula or a pharmaceutically acceptable acid addition salt thereof. 15. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable carrier is a pharmaceutically acceptable carrier. A carrier according to claim 1, characterized in that it has the formula or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized in that it has the formula: ## EQU1 ## and pharmaceutically acceptable salts thereof. A compound according to claim 1, in which the formula has the formula: f. The compound according to claim 1, having the formula C 1 &lt; tb &gt; &lt; tb &gt; / K ,. ^ Ne * <I V - 4 · \ /! and / or a pharmaceutically acceptable salt thereof. Compound according to claim 1, characterized in that it has the formula or a pharmaceutically acceptable salt thereof. under 3 points from the point of view of the distance between them, The present invention relates to a medicament for the treatment of pain and inflammation in the treatment of a condition in which the preparation of the medicament for the treatment of pain is directed to the preparation of a medicament for pain. The use of an effective amount of a compound or a pharmaceutically acceptable salt of the compound according to claims 1, 2 or 3, wherein the amount of the compound of the compound of the formula 16-20 for the preparation of a medicament in which a cell capable of expressing an opioid receptor is further contacted. Use according to claim 23, characterized in that the receptor is a receptor of a K-opioid receptor, a receptor of δ-opioid receptor or an ORR-1 receptor. A process for the preparation of a composition comprising the mixture of a compound or a pharmaceutically acceptable salt of the compound of claims 1, 2 or 16-20 with a carrier or excipient pharmaceutically acceptable salts. A compound according to any one of claims 1, 2 or 16 to 20 or a pharmaceutically acceptable salt thereof, which is characterized in that it is a salt thereof. An effective amount of the compound of formula (I) according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 12, 12, 13, 13, a non-opioid analgesic amount, an opioid analgesic amount and an effective amount of an opioid isozole or an agent.